EUS–TA in unresectable pancreatic cancer requires not only a tissue diagnosis but also tissue collection in anticipation of comprehensive genomic profiling. However, the optimal puncture target remains controversial. Therefore, the Primary and Metastatic Lesions in Pancreatic Cancer (PRIMATE) study was designed to clarify the optimal target by comparing the success rates for meeting OncoGuide NCC Oncopanel (NOP) analysis criteria on pre-check primary and metastatic lesion specimens obtained during the same EUS–TA session in patients with invasive pancreatic ductal adenocarcinoma. In this ongoing prospective study, two specimens, each from primary and metastatic lesions, are obtained by EUS–TA (typically using a 19G fine-needle biopsy needle) in patients with invasive pancreatic ductal adenocarcinoma. The primary endpoint is the proportion of EUS–TA specimens that meet NOP analysis criteria during pre-check (i.e., tumor cellularity ≥ 20% and tissue area ≥ 4 mm2), which are then compared between primary and metastatic lesions. This study has been approved by the National Cancer Center Institutional Review Board (Research No. 2022-168). The results of this study will be reported at an international conference and published in an international peer-reviewed journal. The trial registration number is UMIN 000048966.

Pancreatic cancer is the fourth most common cause of cancer mortality worldwide. Furthermore, patients with pancreatic cancer experience limited benefit from current chemotherapeutic approaches because of drug resistance. Therefore, an effective therapeutic strategy for patients with pancreatic cancer is urgently required. Deguelin is a natural chemopreventive drug that exerts potent antiproliferative activity in solid tumors by inducing cell death. However, the molecular mechanisms underlying this activity have not been fully elucidated. Here we show that deguelin blocks autophagy and induces apoptosis in pancreatic cancer cells in vitro. Autophagy induced by doxorubicin plays a protective role in pancreatic cancer cells, and suppressing autophagy by chloroquine or silencing autophagy protein 5 enhanced doxorubicin-induced cell death. Similarly, inhibition of autophagy by deguelin also chemosensitized pancreatic cancer cell lines to doxorubicin. These findings suggest that deguelin has potent anticancer effects against pancreatic cancer and potentiates the anti-cancer effects of doxorubicin. These findings provide evidence that combined treatment with deguelin and doxorubicin represents an effective strategy for treating pancreatic cancer.

Aim of study:Aim of this meta-analysis is to evaluate post-operative procalcitonin as a marker to predict post- operative infectious complications after pancreatic surgeries.Material and Methods:Systemic literature search was performed using MEDLINE, EMBASE and to identify studies evaluating the diagnostic accuracy of Procalcitonin (PCT) as a predictor for detecting infectious complications on postoperative days (POD) 3 and 5 following pancreatic surgery. A meta-analysis was performed using random effect model and pooled predictive parameters for POD 3 and 5 were derived. Geometric means were calculated for PCT cut offs. Results:6 studies included day 3 PCT analysis, 2 studies included both day 3 and day 5 analysis. Total data of 471 patients were derived. 161 patients developed infectious complications. Pooled sensitivity, specificity, pooled area under curve, diagnostic odds ratio (DOR), positive and negative like hood ratio of day 3 PCT were 74%,79%,0.8453, 11.03,3.17 and 0.31 respectively. Pooled sensitivity, specificity, diagnostic odds ratio (DOR), positive and negative like hood ratio of day 5 PCT were 83%,70%,12.91,2.91 and 0.25 respectively. Geometric means for PCT cut off for day 3 and 5 were 0.80 and 0.43. Conclusion:Postoperative procalcitonin particularly day 3 procalcitonin levels predict post-operative infectious complications following pancreatic surgeries.

Background and aim: The albumin-globulin ratio (AGR) is one of the indicators of inflammation and immunity and it has a prognostic significance in many malignant diseases. Previous studies have shown the relationship between inflammatory mediators and POPF. This study aimed to evaluate the relation of AGR, which is a relatively new indicator, with postoperative pancreatic fistula (POPF). Methods: Pancreaticoduodenectomy (PD) patients between 2017 and 2020 were retrospectively analyzed and divided into two groups as those with and without clinically relevant POPF (CR-POPF). They were compared in terms of preoperative-postoperative AGR and clinicodemographic characteristics. AGR was calculated as Albumin / (Total protein-albumin) and the cutoff point for AGR was determined according to Youden’s index. Results: CR-POPF developed in 21% of 121 patients who underwent PD. There was no difference between the groups in terms of age, gender, comorbid disease status, pancreatic duct width, and anastomosis technique. Preoperative and postoperative day-3 (POD3) albumin levels and AGR were found to be significantly lower in the CR-POPF group. Multivariate analysis showed that AGR and pancreatic tissue stiffness are independent risk factors for the development of POPF. Conclusions: Low AGR is an independent risk factor for the development of CR-POPF. To reduce the incidence of POPF, this ratio should be tried to be kept at an optimal level.

Pancreatic neuroendocrine neoplasms (pNENs) are rare tumors accounting for only 1-2% of all pancreatic tumors. pNENs are pathologically heterogeneous and are categorized into three groups (neuroendocrine tumor: NET G1, NET G2 and neuroendocrine carcinoma: NEC) on the basis of Ki-67 proliferation index and mitotic count according to the 2010 WHO classification of gastroenteropancreatic NENs. NEC in this classification includes both histologically well-differentiated and poorly differentiated subtypes, and modification of the WHO 2010 classification is under discussion based on genetic and clinical data. Genomic analysis has revealed NETs G1/G2 have genetic alterations in chromatin remodeling genes such as MEN1, DAXX and ATRX, whereas NECs have an inactivation of TP53 and RB1, and these data suggest that different treatment approaches would be required for NET G1/G2 and NEC. While there are promising molecular targeted drugs, such as everolimus or sunitinib, for advanced NET G1/G2, treatment stratification based on appropriate predictive and prognostic biomarkers is becoming an important issue. The clinical outcome of NEC is still dismal, and a more detailed understanding of the genetic backround together with preclinical studies to develop new agents, including those already under investigation for SCLC, will be needed to improve the prognosis.

Acinar cell carcinoma (ACC) accounts for about 1% of pancreatic cancers. The molecular and clinical features of ACC are less characterized than pancreatic ductal adenocarcinoma. We retrospectively evaluated the clinical and molecular features of ACC patients who underwent germline and/or somatic molecular testing at The University of Texas MD Anderson Cancer Center from 2008 to 2022. Patient information was extracted from our institutional database with the approval of Institutional Review Board. We identified 16 patients with available molecular testing results. Fourteen patients had metastatic disease, 1 had borderline resectable disease, and 1 had localized resectable disease at diagnosis. Fifteen patients were wild type for KRAS (1 patient had unknown KRAS status). Somatic/germline mutations of DNA damage repair genes (BRCA1/2, PALB2, and ATM) were present in 5 of 12 patients tested for these genes. One patient was found to have RET fusion and responded favorably to selpercatinib for over 42 months. The median overall survival (OS) was 24 months for patients with metastatic disease. One of the additional two cases which had BostonGene tests was found to have NTRK1 fusion. RNA and TME analysis by BostonGene of the two cases reported immune desert features and relatively lower RNA levels of CEACAM5, CD47, CD74 and MMP1 and higher CDH6 compared with PDAC.

This review explores the challenges and emerging trends in pancreatic cancer therapy. In particular, we focus on the tumor microenvironment and the potential of immunotherapy in pancreatic cancer. We discuss novel strategies targeting the desmoplastic barrier and immunosuppressive cells to enhance immune cell infiltration and activation. Recent clinical trials, particularly those involving novel immunotherapeutic agents and tumor vaccines, are examined to understand their efficacy and limitations. This review aims to highlight the ongoing efforts to refine immunotherapy approaches for better patient outcomes.

Familial pancreatic cancer (FPC) represents a significant yet underexplored area in pancreatic cancer research. Basic research efforts are notably limited, and when present, they are predominantly centered on BRCA1 and BRCA2 mutations due to the scarcity of other genetic variants associated with FPC, leading to a limited understanding of the broader genetic landscape of FPC. This review examines the current state of FPC research, focusing on the molecular mechanisms driving pancreatic ductal adenocarcinoma (PDAC) progression. It highlights the role of homologous recombination (HR) and its therapeutic exploitation via synthetic lethality with PARP inhibitors in BRCA1/2-deficient tumors. The review discusses various pre-clinical models of FPC, including conventional two-dimensional (2D) cell lines, patient-derived organoids (PDOs), patient-derived xenografts (PDXs), and genetically engineered mouse models (GEMMs) as well as new advancements in FPC research.

Pancreatic cancer is one of the most aggressive and lethal forms of cancer, with a five-year survival rate of less than 10%. Despite advances in treatment modalities, the prognosis for pancreatic cancer patients remains poor, highlighting the urgent need for innovative approaches for early diagnosis and targeted therapies. In recent years, there has been significant progress in understanding the molecular mechanisms underlying pancreatic cancer development and progression. This paper reviews the current knowledge of molecular targets for the diagnosis and treatment of pancreatic cancer.

Metabolomics profiling for accurate and reliable quantification of organic acids that carry a carboxylic acid functional group in complex biological samples, remains a major analytical challenge in clinical chemistry research. Several procedural barriers associated with quantification of clinically important carboxylic containing metabolites (CCMs) including spontaneous decarboxylation during ionization, poor chromatographic resolution, and retention on a reverse-phase column, limit the sensitivity, specificity, and reproducibility of multiple-reaction monitoring (MRM) based LC-MS assay development. We report a targeted metabolomics-based analytical method for the quantification of CCMs using phenylenediamine derivatization. Accurate and sensitive quantification of CCMs is successfully demonstrated in an array of biological matrices. Recovery of metabolites from different matrices (plasma, serum, urine, saliva, tissues, and cell extracts), ranged from 90% to 105%, with all the CVs ≤ 10%. The method showed linearity over a broad dynamic range from 0.1 ng/mL to 10 µg/mL with linear regression coefficients of 0.99 for most of the metabolites tested herein, that covers broad-based applicability with the analysis of biological samples. In most cases the LODs were as low as 0.01 ng/mL. The phenylenediamine-based derivatization of carboxyl acid library consisting of more than 70 endogenous metabolites was constructed for metabolite identification, which spanned more than 40 biological pathways. The library included a wide-variety of structurally variant CCMs such as amino acids/conjugates, short to medium chain organic acids, di/tri-carboxylic acids/conjugates, fatty acids and some ring-containing CCMs. We compared the CCMs profiles of pancreatic cancer cells with normal pancreatic epithelial cells to test and validate the biological utility of this method. The comparative profiling between cancerous and normal cells resulted in the identification of potential biomarkers in pancreatic cancer, and their correlation with several key metabolic pathways such as central carbon energy metabolism, protein metabolism, including TCA cycle, glycolysis, Gln-Glu pathway, and biosynthesis of amino acids and unsaturated fatty acids was established. The method, described herein, for the first time enables the sensitive and highly specific quantification of CCMs on small sample size with high reproducibility in a high throughput manner. Given the biological and functional significance of this class of metabolites, this mass spectrometry based targeted quantitative assay, fills an important gap and is likely to support a wide range of applications for basic, clinical, and translational research.

Most patients with pancreatic cancer at some point present with symptoms related to exocrine pancreatic insufficiency (EPI). These include diarrhea, abdominal bloating, indigestion, steatorrhea, weight loss, and anorexia. Even though up to 80% of pancreatic cancer patients eventually present with symptoms related to exocrine pancreatic insufficiency, only 21% are prescribed pancreatic enzyme replacement therapy. This treatment is profoundly underutilized in the palliative care of these patients. The objective of this review is to discuss the pharmacology, pharmacokinetics, side effects, available evidence of effectiveness of pancreatic enzyme use for patients with pancreatic cancer, and challenges along with proposed solutions regarding its use. Pancrelipase is an expensive drug, and it is inactive if not taken correctly. The impact of symptoms of EPI can lead to poorer overall well-being. Pharmacists play a crucial role in properly educating patients on the correct use of pancreatic enzyme replacement therapy. Pancreatic enzyme replacement therapy (PERT) is a key strategy in managing symptoms of EPI and can improve quality of life, which is a central focus in palliative care.

It is estimated that pancreatic cancer will be the 2^nd leading cause of cancer-related deaths globally by 2030, highlighting the ongoing lack of effective treatment options in this devastating condition. There is a lack of reliable prognostic or predictive markers in pancreatic cancer to guide management decisions, whether for systemic chemotherapy, molecularly targeted therapies, or immunotherapies. To date, the results for targeted agents and immunotherapies in unselected populations of chemo-refractory pancreatic cancer have not met expectations. The reasons for this lack of efficacy of immunotherapy in pancreatic cancer are incompletely understood. The challenges in pancreatic cancer include the physical barrier created by the dense desmoplastic stroma surrounding the tumor, chemokine-mediated exclusion of T cells, poor antigenicity, paucity of infiltrating T cells within the tumor, ultimately leading to an immunosuppressive microenvironment. A better understanding of the role of inflammation in pancreatic cancer, its tumor microenvironment and individualized patient-related features, be they molecular, clinical or histopathological would enable a more effective tailored approach to the management of pancreatic cancer. In this review, the role of inflammation, the immune tumor microenvironment and potential immune biomarkers in pancreatic cancer are explored.

Pancreatic cancer (PC) is considered one of the most challenging and formidable malig-nancies to treat because it is usually diagnosed at terminal stage, thus it is characterized with a poor prognosis with 5% of patients living over 5 years. The late diagnosis leads to a lower suc-cess rate of resectability, hence chemotherapy or chemoradiotherapy are the only hopes for most PC patients. However, the available drug combinations for PC treatment did not provide satisfactory clinical outcomes. There is a pressing and urgent need to discover new chemothera-peutics which fight PC with tolerable side effects and less liability for resistance. Pentacyclic triterpenes (PTs) are privileged structures with a multitude of biological activities mitigating several ailments, particularly in neoplasm field. They are characterized by a high therapeutic window and their activity can be highly enhanced through structural modifications. Indeed, several parent PTs such as oleanolic acid, ursolic acid, lupeol, betulinic acid, and celastrol proved effective against different PC phenotypes inhibiting their proliferation, invasion, and metastasis mainly via KRAS modulation. Some PTs worked as adjuvant chemosensitizers in gemcitabine-resistant or TRAIL-resistant cells. Owing to their potential in PC treatment, we pre-sent this review article summarizing PC pathogenesis and the promising role of PTs in the man-agement of PC when used either solely or in combination with other chemotherapies such as gemcitabine and 5-Fluorouracil.

Pancreatic cancer is the third leading cause of cancer-related deaths in the United States. Pancreatic ductal adenocarcinoma (PDA) is the most common (90%) and aggressive type of pancreatic cancer. Genomic analyses of PDA specimens have identified the recurrent genetic mutations that drive PDA initiation and progression. However, the underlying mechanisms that further drive PDA metastasis remain elusive. Despite many attempts, no recurrent genetic mutation driving PDA metastasis has been found, suggesting that PDA metastasis is driven by epigenetic fluctuations rather than genetic factors. Therefore, establishing epigenetic mechanisms of PDA metastasis would facilitate the development of successful therapeutic interventions. In this review, we provide a comprehensive overview on the role of epigenetic mechanisms in PDA as a critical contributor on PDA progression and metastasis. In particular, we explore the recent advancements elucidating the role of nucleosome remodeling, histone modification, and DNA methylation in the process of cancer metastasis.

Cytologic diagnosis of extra‐adrenal paraganglioma presenting as a peripancreatic mass is challenging with a high rate of diagnostic error. We present a case of a peripancreatic mass identified by radiology as a gastrointestinal stromal tumor. Endoscopic ultrasound‐guided fine needle aspiration (FNA) of the mass showed a moderately cellular tumor composed of small to medium sized neoplastic cells with round to oval nuclei arranged singly and in loose clusters. The cells were positive for neuroendocrine markers (synaptophysin and chromogranin) and negative for CD117. A diagnosis of a neoplasm with a neuroendocrine tumor (NET) was made on FNA cytology. The subsequent surgical resection of the tumor revealed peripancreatic paraganglioma with immunohistochemistry positive for synaptophysin, chromogranin, and S100. The latter delineates the sustentacular cells. Although paraganglioma is a well recognized tumor, a detailed comparison of peripancreatic paraganglioma versus pancreatic/gastrointestinal NET is still lacking.

Pancreatic cancer (PC) has a poor prognosis and displays resistance to immunotherapy. A better understanding of tumor-derived extracellular vesicles (EVs) effects on immune responses might contribute to improved immunotherapy. EVs derived from Capan-2 and BxPC-3 PC cells isolated by ultracentrifugation were characterized by atomic force microscopy, western blot (WB), nanoparticle tracking analysis and label-free proteomics. Fresh PBMCs from healthy donors were treated with PC- or control-derived heterologous EVs followed by flow cytometry analysis of CD8+ and CD4+ lymphocytes. Proteomics of lymphocytes sorted from EV-treated, or -untreated PBMCs was performed and IFN-γ concentration was measured by ELISA. Notably, most of the proteins identified in Capan-2 and BxPC-3 EVs by proteomic analysis were connected in a single functional network (p=1x10-16) and were involved in “Immune System” (FDR: 1.10x10-24 and 3.69x10-19, respectively). Interestingly, treatment of healthy donor-derived PBMCs with Capan-2 EVs, but not with BxPC-3 EVs or heterologous control EVs induced early activation of CD8+ and CD4+ lymphocytes. Proteomics of lymphocytes sorted from EV-treated PBMCs was consistent with their activation by Capan-2 EVs, indicating IFN-γ among major upstream regulators, as confirmed by ELISA. Proteomic and functional analyses indicate that PC-EVs have pleiotropic effects, and some may activate early immune response, which might be relevant for the development of highly needed immunotherapeutic strategies in this immune-cold tumor.

(1) Background: The aim of this study was to compare the survival benefit of radical ante-grade-modular pancreato-splenectomy (RAMPS) with conventional distal pancreato-splenectomy (cDPS) in left-sided pancreatic cancer. (2) Methods: A retrospective propensity score matching (PSM) analysis was conducted on 333 patients who underwent RAMPS or cDPS for left-sided pancreatic cancer at four tertiary cancer centers. The study assessed prognostic factors and com-pared survival and operative outcomes. (3) Results: After PSM, 99 patients were matched in each group. RAMPS resulted in a higher retrieved lymph node count than cDPS (15.0 vs. 10.0, p < 0.001). No significant differences were observed between the two groups in terms of R0 resection rate, blood loss, hospital stay, or morbidity. The 5-year overall survival rate was similar in both groups (cDPS vs. RAMPS, 44.4% vs. 45.2%, p = 0.853), and disease-free survival was also comparable. Multivariate analysis revealed that ASA score, preoperative CA19-9, histologic differentiation, R1 resection, adjuvant treatment, and lymphovascular invasion were significant prognostic factors for overall survival. Preoperative CA19-9, histologic differentiation, T-stage, adjuvant treatment, and lymphovascular invasion were independent significant prognostic factors for disease-free survival. (4) Conclusions: Although RAMPS resulted in a higher retrieved lymph node count, survival outcomes were not different between two groups. RAMPS was a surgical option to achieve R0 resection rather than a standard procedure. Adjuvant treatment was an independent prognostic factor for both overall and disease-free survival.

Neurological disorders are the leading cause of cognitive and physical disability worldwide, affecting 15% of the global population. Due to the demographics of aging, the prevalence of neurological disorders, including neurodegenerative diseases, will double over the next two decades. Unfortunately, while available therapies provide symptomatic relief for cognitive and motor impairment, there is an urgent unmet need to develop disease-modifying therapies that slow the rate of pathological progression. In that context, biomarkers could identify at-risk and prodromal patients, monitor disease progression, track response to therapy, and parse causality of molecular events to identify novel targets for further clinical investigation. Thus, identifying biomarkers that discriminate between diseases and reflect specific stages of pathology would catalyze the discovery and development of therapeutic targets. This review will describe the prevalence, known mechanisms, ongoing or recently concluded therapeutic clinical trials, and biomarkers of three of the most prevalent neurodegenerative diseases, including Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson’s disease (PD).

Pancreatic cancer stands out as one of the most lethal forms of malignancies, representing 2% of all cancer cases and contributing to 5% of cancer-related fatalities. Therefore, early detection of pancreatic cancer is crucial for enhancing treatment outcomes. Various hereditary cancer syndromes have been linked to an elevated risk of developing pancreatic cancer, suggesting potential benefits from surveillance strategies for individuals at risk. Presently, precision medicine employs PARP inhibitor therapy for pancreatic cancer patients carrying germline variants in Homologous Recombination Repair (HRR) genes. Our objective was to ascertain the occurrence of germline pathogenic/likely pathogenic variants in genes predisposing to cancer among pancreatic cancer patients. Methodologically, we analyzed 184 pancreatic cancer patients referred to our laboratory for genetic examination. Utilizing a Next-Generation Sequencing (NGS) approach, we scrutinized 52 genes implicated in hereditary cancer predisposition. Our findings revealed that 21% of the patients analyzed harbored germline pathogenic/likely pathogenic variants. Within this subset, 48% exhibited positive results in pancreatic cancer susceptibility genes, namely ATM (17%), BRCA1 (12%), BRCA2 (7%), CDKN2A (7%), and PALB2. Significantly, 64.3% of the pathogenic variants were associated with genes involved in the HRR pathway (ATM, BRCA1, BRCA2, BRIP1, CHEK2, FANCL, MRE11, PALB2, RAD50, RAD51B and RAD51C). In conclusion, our study underscores the significance of multigene genetic testing for pancreatic cancer patients, with 21% of individuals yielding findings linked to pancreatic or other cancer predisposition. Moreover, patients carried pathogenic/likely pathogenic variants in HRR genes, potentially benefiting from targeted therapies such as PARP inhibitors or platinum-based treatments.

Early detection of pancreatic ductal adenocarcinoma (PDAC) requires further examination after selecting cases with risk factors for the condition, such as family history, hereditary pancreatic carcinoma syndrome, intraductal papillary mucinous neoplasms, or chronic pancreatitis. The Japan Study Group on the Early Detection of Pancreatic Cancer has investigated and clarified the clinicopathological features for the early diagnosis of PDAC. Further approaches for the early diagnosis of PDAC are warranted.

Detection of pancreatic cancer (PC) at a resectable stage is still difficult because of the lack of accurate detection tests. The development of accurate biomarkers in low or non-invasive biofluids is essential to enable frequent tests, which would help increase the opportunity of PC detection in early stages. Polyamines have been reported as possible biomarkers in urine and saliva samples in various cancers. Here, we analyzed salivary metabolites, including polyamines, using capillary electrophoresis-mass spectrometry. Salivary samples were collected from patients with PC (n=39), chronic pancreatitis (CP, n=14) and controls (C, n=26). Polyamines, such as spermine, N1-acetylspermidine, and N1-acetylspermine, showed a significant difference between PC and C, and the combination of four metabolites including N1-acetylspermidine showed high accuracy in discriminating PC from the other two groups. These data showed the potential of saliva as a screening test for PC.

Gene regulation is vital for cellular function and homeostasis, involving diverse mechanisms controlling specific gene products and contributing to tissue-specific gene expression. Dysregulation leads to diseases, emphasizing the need for understanding these mechanisms. Non-coding regions, notably enhancers and super-enhancers (SEs), act as crucial gene regulators, orchestrating transcriptional activity via transcription factors (TFs). SEs, with high activity, are pivotal in cell identity and disease progression. Current computational approaches focus on individual regulators like TFs and miRNAs, neglecting SE interactions. We emphasize incorporating SEs into models to enhance understanding. Experimental studies have recently linked miRNAs and TFs to SEs. Chromatin immunoprecipitation followed by sequencing (ChIP-Seq) provides valuable SE information. In this review, we categorize computational methods leveraging TF and miRNA data into three areas and explore challenges integrating enhancers/SEs. These include unraveling indirect regulatory networks, identifying network motifs, and enriching pathway identification by dissecting gene regulators, including SEs. We hypothesize that addressing these challenges will enhance our understanding of gene regulation, aiding in identifying therapeutic targets and disease biomarkers. We believe that understanding the role of ChIP-Seq data in predicting the effect of miRNA on gene regulation is crucial to construct statistical/computational model that would tackle these challenges.

Background: Colorectal cancer (CRC) patients experienced multiple chemotoxicity affecting treatment compliance, survival, and quality of life (QOL). Prior research shows clinician-reported chemotoxicity (i.e., grading scales or diagnostic codes) predicts rehospitalization and cancer survival. However, a comprehensive synthesis of clinician-reported chemotoxicity is still lacking. Objectives: We conducted a systematic review and meta-analysis to determine the chemotoxicity's prevalence and risk factors in CRC. Methods: A systematic search from 2009 to 2024 yielded 30 studies for review, with 25 included in the meta-analysis. Results: Pooled prevalences of overall, non-hematological, and hematological moderate-to-severe toxicities were 45.7%, 39.2%, and 25.3%, respectively. The most common clinician-reported chemotoxicities were gastrointestinal (GI) toxicity (22.9%) and neuropathy or neutropenia (17.9%). Significant risk factors at baseline were malnutritional status, frailty, impaired immune or hepato-renal functions, short telomere lengths, low gut lactobacillus levels, age, female sex, aggressive chemotherapy, and low QOL. Age was associated with neutropenia (β: -1.44) and GI toxicity (β:1.85) (Ps 65 y.o.) had higher prevalences of overall (OR: 1.14) and GI (OR: 1.65) toxicities, but a lower prevalence of neutropenia (OR: 0.65) than younger adults (Ps

Introduction: Gastric cancer (GC) is one of the most frequently diagnosed cancers in the world. Although the incidence is decreasing in developed countries, treatment results are still unsatisfactory. The standard treatment for locally advanced gastric cancer (LAGC) is gastrectomy with perioperative chemotherapy. Aim: Assessment of selected microRNAs (miRNAs) in chemoresistance in archival material from LAGC. Material and method: The research group consisted of archival material from 10 patients with LAGC. Histological material from each patient was used from a biopsy performed during gastroscopy and after surgery preceded by 4 cycles of neoadjuvant chemotherapy (NAC) according to the FLOT or FLO regimen. The expression of selected miRNAs was assessed in the tissue material, such as miRNA-21-3p, miRNA-21-5p, miRNA-106a-5p, miRNA-122-3p, miRNA-122-5p, miRNA-143-3p, miRNA-143-5p, miRNA-203a-3p, miRNA-203-5p, miRNA-551b-3p, miRNA-551b-5p and miRNA-574-3p. miRNA expression was assessed by quantitative chain reaction polymerase reverse transcriptase (qRT-PCR). The response to NAC was assessed by computed tomography of the abdomen, chest and histopathology after gastrectomy. The statistical analyses were performed using GraphPad Prism 9.The significance limit was set at p

Epithelial ovarian cancer (EOC) has not significantly benefited from advances in immunotherapy, mainly because of the lack of well-defined actionable antigen targets. Using proteogenomic analyses of primary EOC tumors, we previously identified 91 aberrantly expressed tumor-specific antigens (TSAs) originating from unmutated genomic sequences. Most of these TSAs derive from non-exonic regions, and their expression results from cancer-specific epigenetic changes. The present study aimed to evaluate the immunogenicity of 48 TSAs selected according to two criteria: presentation by highly prevalent HLA allotypes and expression in a significant fraction of EOC tumors. Using targeted mass spectrometry analyses, we found that pulsing with synthetic TSA peptides leads to a high-level presentation on dendritic cells. TSA abundance correlated with the predicted binding affinity to the HLA allotype. We stimulated naïve CD8 T cells from healthy blood donors with TSA-pulsed dendritic cells and assessed their expansion with two assays: MHC-peptide tetramer staining and TCR Vβ CDR3 sequencing. We report that these TSAs can expand sizeable populations of CD8 T cells and, therefore, represent attractive targets for EOC immunotherapy.

Aims and objectives: The primary aim of our study was to evaluate morbidity and mortality following feeding jejunostomy in pancreaticoduodenectomy compared to the control group. We also evaluated individual complications like delayed gastric emptying; post operative pancreatic fistula, superficial and deep surgical site infection. Material and Methods: The study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and MOOSE guidelines. Heterogeneity was measured using Q tests and I2.the random-effects model was used. Results: Four studies including Total of 1639 patients were included in the analysis. Total 843 patients were included in Feeding jejunostomy group and 796 patients included in control group without feeding jejunostomy. Over all morbidity was significantly higher in feeding jejunostomy group. (P = 0.001). There was no significant difference between both the groups. (P=0.07). Delayed gastric emptying was significantly higher in feeding jejunostomy group. [P=0.021]. There was no significant difference in development of pancreatic fistula between the two groups. Deep surgical site infection was significantly higher in feeding jejunostomy group. (P=0.013). Hospital stay was significantly more in feeding jejunostomy group (p<0.0001). There was no significant difference between readmission; TPN requirement and time to start oral feed. Conclusion: Feeding jejunostomy seems to be associated with increased morbidity and increased length of stay.

Pancreatic cancer is one of the most fatal common cancers affecting both men and women, representing about 3 percent of all new cancer cases in the United States. In this study, we aimed to investigate the association of pancreatic cancer risk with alcohol consumption as well as folate intake. We performed a case-control study of 384 patients diagnosed with pancreatic cancer from May 2004 to December 2009 and 983 primary care healthy controls. Our findings showed no significant association between risk of pancreatic cancer and either overall alcohol consumption or type of alcohol consumed (drinks/day). Our study showed dietary folate intake was modestly but significantly inversely associated with pancreatic cancer (OR=0.99, P <.0001). The current study supports the hypothesis that pancreatic cancer risk is reduced with higher food-based folate intake.

Although there is a several array of diagnostic and therapeutic choices for pancreatic cancer in recent years, a crucial medical approach for the refractory disease is still needed. Oligonucleotide therapeutics, such as those based on antisense RNAs, RNA interference, aptamers and decoys, are promising agents against pancreatic cancer because they identify a specific nucleotide sequence or protein and interfere with gene expression as molecular-targeted agents. Within just the past quarter-century, the diversity and feasibility of these drugs as diagnostic or therapeutic tools have dramatically increased. Actually, there have been several clinical and preclinical studies of oligonucleotides for patients with pancreatic cancer so far. To support the discovery of effective diagnostic or therapeutic options by using oligonucleotide-based strategies in the absence of satisfactory therapies for long-term survival and the rising trend of diseases, we summarize the current clinical trials of oligonucleotide therapeutics for pancreatic cancer patients with underlying preclinical or scientific data and focus on the possibility of oligonucleotides to target pancreatic cancer in clinical implications.

Pancreatic cancer is an intractable disease with the worst prognosis of all cancers. The currently used treatment regimens do not significantly impact patient survival, and therefore, effective treatment strategies are urgently needed. Drug repurposing, which identifies new indications for existing and approved drugs, has proven to be a promising approach to anti-cancer drug discovery. Indeed the antihelmintic drug, pyrvinium pamoate has shown promise as an anti-pancreatic cancer drug, but to date, the inhibition of mitochondrial function is the only mechanism of action described in pancreatic cancer. This study showed, using pancreatic cancer 2D cell cultures and 3D spheroids, that pyrvinium pamoate exhibited short- and long-term cytotoxicity, inhibited epithelial-to-mesenchymal transition and cell invasion and migration. Mechanistically, pyrvinium pamoate induced DNA damage, inhibited the PI3K/AKT cell survival pathway, and triggered cell cycle arrests, as well as apoptotic and autophagic cell death. Importantly, pyrvinium pamoate acted synergistically with the first-line drug, gemcitabine in 2D and 3D pancreatic cancer cell culture models. This study provided evidence that pyrvinium pamoate is effective as a single agent and in combination with gemcitabine for the treatment of pancreatic cancer.

Bladder cancer (BC) is one of the most lethal genitourinary malignancies owing to its propensity for recurrence and poor survival. The biochemical pathway, signal transducer and activator of transcription 3 (STAT3), has gained significance as a molecular pathway that promotes proliferation, invasion, and chemoresistance. In this study, we explored the targeting of STAT3 with TTI-101 and SH5-07 in bladder cancer (BCa) and elucidated the mechanisms in three-dimensional (3D) spheroid and tumoroid models. We optimized the growth of spheroids from human, rat, and mouse BCa cell lines (J82, NBT-II, and MB49, respectively), and tumoroids from BBN (N-butyl-N-(4-hydroxybutyl)-nitrosamine) induced rat bladder tumors. Cell viability was assessed using MTT and trypan blue assays. ATP production, ROS production, and calcium AM (CA)/EtBr staining were used to measure the spheroid and organoid inhibition and mitochondrial function. Western blot analysis was performed to evaluate the pharmacodynamic markers involved in cell proliferation, apoptosis, cancer stem cells (CSCs), and STAT3 signaling in BCa. We found that targeting STAT3 (using TTI-101 and SH5-07) significantly reduced the proliferation of BCa spheroids, and tumoroids, which was accompanied by decreased expression of pSTAT3, Cyclin D1, and PCNA. Our data also demonstrated that treatment with STAT3 inhibitors induced ROS production and cell death in BCa spheroids and organoids. STAT3 inhibition induced cell death was associated with the activation of caspase 3/7 and PARP cleavage. Moreover, TTI-101 and SH5-07 targets cancer stem cells by downregulating the expression of CD44 and CD133 in 3D models. This study provides the first evidence for the prevention of bladder cancer with small-molecule inhibitors TTI101 and SH5-07 via suppression of CSCs and STAT3 signaling.

During HIV-1 virus assembly the genomic RNA (vRNA) is selected for packaging by the viral protein Gag because it contains a specific packaging signal, Psi. While there have been numerous studies of Gag-Psi interactions, there is almost no information on kinetic aspects of this interaction. We have investigated the kinetics of Gag binding to different RNAs using switchSENSE DRX2 technology. We measured the association rate of Gag binding to monomeric Psi, to a “Multiple Binding Site Mutant” Psi that is inactive for genome packaging in vivo, and to a scrambled Psi. We discovered that Gag binds more rapidly to Psi RNA than to the mutant or scrambled RNAs. Furthermore, rapid Gag association kinetics are retained within sub-regions of Psi: Gag associates more rapidly with RNA containing only the 3’ two of the three Psi stem-loops than with monomeric RNA containing the 5’ two stem-loops or a scrambled RNA. No differences were detectable with individual Psi stem-loops. Interestingly, the rate of binding of Gag molecules to Psi increases with increasing Gag concentration, suggesting cooperativity in binding. The results are consistent with the hypothesis that selectivity in packaging derives from kinetic differences in initiation of particle assembly.

Adjuvant chemotherapy is currently used in all patients with resected pancreatic cancer who are able to begin treatment within 3 months after surgery. Since the recent publication of the PRODIGE 24 trial results, modified FOLFIRINOX has become the standard-of-care in the non-Asian population with localized pancreatic adenocarcinoma following surgery. Nevertheless, there is still a risk of toxicity, and feasibility may be limited in heavily pre-treated patients. In more frail patients, gemcitabine-based chemotherapy remains a suitable option, for example gemcitabine or 5FU in monotherapy. In Asia, although S1-based chemotherapy is the standard of care it is not readily available outside Asia and data are lacking in non-Asiatic patients. In patients in whom resection is not initially possible, intensified schemes such as FOLFIRINOX or Gemcitabine-Nabpaclitaxel have been confirmed as options to enhance the response rate and resectability, promoting research in adjuvant therapy. In particular, should oncologists prescribe adjuvant treatment after a long sequence of chemotherapy +/- chemoradiotherapy and surgery? Should oncologists consider the response rate, the R0 resection rate alone, or the initial chemotherapy regimen? And finally, should they take into consideration the duration of the entire sequence, or the presence of limited toxicities of induction treatment? The aim of this review is to summarize adjuvant management of resected pancreatic cancer and to raise current and future concerns, especially the need for biomarkers and the best holistic care for patients.

While the mortality rates of cancer are generally declining, pancreatic cancer persists to be an exception with a 5-year-survival rate of less than 7%. Late diagnosis and resistance to conventional therapies contribute to high mortality rates in spite of the remarkable recent advances in cancer management and research. Consequently, there is an urgent need to find new and unconventional therapeutic targets to improve prognosis and survival of pancreatic cancer patients. In this review, we discuss the transcriptional effects of the most widely used epigenetic inhibitors in pancreatic cancer focusing on Bromodomain and Extraterminal domain (BET) and Histone Deacetylase (HDAC) inhibitors, which are currently highly promising therapeutic options. We suggest that these inhibitors can be better utilized at lower doses which exploit their transcriptional modulatory effects on pancreatic cancer transcriptional programs directed by specific factors such as MYC and FOXA1, rather than simply based on their anti-proliferative effects. This approach can potentially help avoid the intolerable adverse events frequently elicited by the use of these treatments at higher doses. In particular, we underscore the crucial role of distal regulatory elements in mediating the specific effects of these epigenetic inhibitors and propose using them in a more selective and prudent manner.

Pancreatic ductal adenocarcinoma (PDA), the most frequent type of pancreatic cancer, is one of the main unfinished businesses in the biomedical and clinical fields, with still discouraging 5 year survival rates and poor therapy efficiency. PDA abundant desmoplasia has for long played the lead in the mechanisms involved in poor drug performance, being the main source of cytokines and chemokines orchestrating rapid and silent tumor progression and guilty of isolating tumor cells into a extense fibrotic reaction resulting in inefficient drug delivery. However, since immunotherapy was proclaimed the breakthrough of the year back to 2013, the focus in the stroma of pancreatic cancer has interestingly moved from activated fibroblasts to the immune compartment, trying to understand the immunosuppressive factors that play part in the strong immune evasion that characterizes PDA. PDA microenvironment is highly immune-suppressive, being basically composed of T regulatory cells (Tregs), tumor-associated macrophages (TAMs) and myeloid-derived suppressive cells (MDSCs), which boycott CD8⁺ T-cell duties in tumor recognition and clearance. Interestingly, preclinical data have highlighted the importance of this immune evasion as the source of resistance to single checkpoint immunotherapies and cancer vaccines and point at pathways inhibiting the immune attack as the key to solve the therapy puzzle. Here, we will discuss the molecular mechanisms involved in PDA immune escape as well as the state of the art of the PDA immunotherapy.

The p53 tumor suppressor protein shows antiviral activity. The replication of viruses is also antagonized by interferons (IFNs) – cytokines, which control immunity genes by the STAT transcription factors. The best studied interferons belong to type I (e.g. IFNα) and type II (IFNγ) groups. IFNα and IFNγ both induce activating phosphorylation of STAT1 on Tyr701. Previously, we noticed that p53 activates SOCS1, which is a negative regulator of STAT1 phosphorylation. Thus, we hypothesized that p53 by activating SOCS1 expression reduces phosphorylation of STAT1 and attenuates activation of genes stimulated either by IFNα or IFNγ. To test this hypothesis, we exposed p53-proficient and p53-deficient cells to strong p53 activators, and either to IFNα or IFNγ. Subsequently, we estimated the phosphorylation status of STAT1 and the expression of genes regulated by either of these cytokines. Strong activation of p53 reduced the phosphorylation of STAT1 on Tyr701, however surprisingly it did not lead to reduced expression of most tested interferon-stimulated genes. On contrary, p53 and IFNγ synergized in the activation of CASP1, IFIT1 and IFIT3 genes. We conclude that the interactions between p53 and interferon-activated pathways are more complicated than initially expected, but the apparent cooperation between p53 and IFNγ deserves further studies.

Introduction Infections caused by multidrug-resistant bacteria (MDR) occur more frequently after pancreaticoduodenectomy (PD) compared to other abdominal surgeries, and infective complications are a leading cause of postoperative morbidity following PD. Pre-operative biliary stent (PBS) placement often leads to biliary contamination, which in turn plays a significant role in postoperative infections. The aim of this study is to evaluate the impact of MDR contamination on short-term postoperative outcomes in patients undergoing PD and to examine the relationship between MDR bacteria, PBS, and bile contamination. Methods This is a retrospective study based on a prospectively maintained database comprising 825 consecutive patients who underwent pancreaticoduodenectomy (PD) between January 2010 and December 2020 at our center. All procedures were conducted with a standardized resection by a dedicated group of surgeons in a specialized pancreatic surgery unit, and the patients were managed according to the same perioperative enhanced recovery protocol. Results MDR bacteria were present in 17.5% of bile cultures, exclusively within the stented group. In our multivariate analysis, the development of a major postoperative complication (MPC) was correlated with the presence of MDR bacteria in the bile (OR 1.66, 95% CI: 1.1-2.52; p = 0.02). MDR bacteria were detected early in the surgical drainage in 144 out of 825 patients (12.1%), with 72.2% having a previous biliary stent placement and 27.8% without stents (p < 0.001). In our multivariate analysis, the development of an MPC was associated with the presence of MDR bacteria in the drainage (OR=1.81, 95% CI: 1.21-2.73, p= 0.0042). Conclusions We demonstrated that MDR contamination worsens the short-term outcomes of patients undergoing PD. Specifically, when MDR bacteria are present in both the bile and drainage, there is a statistically significant increase in the incidence of major postoperative complications (MPC). Our data suggest that the majority of MDR surgical site infections stem from biliary contamination resulting from the placement of a pre-operative biliary stent (PBS).

From their discovery in 2002, BRAF mutations have been identified as clear drivers of oncogenesis in several cancer types. Currently, their incidence rate is nearly 7% of all solid tumors with BRAF V600E constituting approximately 90% of these diagnoses [1]. In melanoma, thyroid cancer, and histiocytic neoplasms, BRAF hotspot mutations are found at a rate of about 50%, while in lung and colorectal cancers they range from 3 to 10% of reported cases [2-5]. Though present in other malignancies such as breast and ovarian cancers, they constitute a small portion of diagnoses (<1%). Given their frequency along with advancements in screening technologies, various methods are used for the detection of BRAF-mutant cancers. Among these are targeted next-generation sequencing (NGS) on tumor tissue or circulating tumor DNA (ctDNA) and immunohistochemistry (IHC)-based assays. With advancements in detection technologies, several approaches have been taken for the treatment of BRAF mutant cancers. In this review we retrace the milestones that led to the clinical development of targeted therapies currently available for these tumors.

Cancer treatment is a significant focus in medicine owing to the increasing global incidence. Patients with advanced cancers that do not respond to conventional therapies have limited options and an unfavorable prognosis. Consequently, researchers are investigating complementary approaches to conventional treatments. One such approach is alkalization therapy, which aims to neutralize the acidic tumor microenvironment (TME) by increasing its pH level. The acidic TME promotes inflammation, tumor progression, and drug resistance. Alkalization therapy has been demonstrated to be effective for various cancers. In addition, natural products, such as triterpenoids, parthenolides, fulvic acid, Taxus yunnanensis, and apple pectin have the potential to alleviate symptoms, maintain physical fitness, and improve treatment outcomes of cancer patients through their anti-inflammatory, antioxidant, and anticancer properties. In this review, we focus on the effects of alkalization therapy and natural products on cancer. Furthermore, we present a case series of advanced cancer patients who received alkalization therapy and natural products alongside standard treatments, resulting in long-term survival. We posit that alkalization therapy together with the supplementation of natural products may confer benefits to cancer patients by mitigating the side effects of chemotherapy and complementing standard treatments. However, further research is warranted to validate these clinical findings.

Podocalyxin (PODXL) overexpression is associated with poor clinical outcomes in various tumors. PODXL is involved in tumor malignant progression through the promotion of invasiveness and metastasis. Therefore, PODXL has been considered as a promising target of monoclonal antibody (mAb)-based therapy. However, PODXL also plays an essential role in normal cells such as vascular and lymphatic endothelial cells.Therefore, cancer-specificity or selectivity is required for the reduction of adverse effects on normal cells. Here, we developed an anti-PODXL cancer-specific mAb (CasMab), PcMab-6 (IgG₁, kappa), by immunizing mice with soluble PODXL ectodomain derived from a glioblastoma LN229 cell.PcMab-6 reacted with the PODXL-positive LN229 cells, but not with PODXL-knockout LN229 cells in flow cytometry. Importantly, PcMab-6 recognized pancreatic ductal adenocarcinoma (PDAC) cell lines (MIA PaCa-2, Capan-2, and PK-45H), but did not react with normal lymphatic endothelial cells (LECs). In contrast, one of the non-CasMabs, PcMab-47 showed high reactivity to both the PDAC cell lines and LECs. Next, we engineered PcMab-6 into a mouse IgG_2a type (PcMab-6-mG_2a) and a humanized IgG₁-type (humPcMab-6) mAbs, and further produced the core fucose-deficient types (PcMab-6-mG_2a-f and humPcMab-6-f, respectively) to potentiate the antibody-dependent cellular cytotoxicity (ADCC). Both PcMab-6-mG_2a-f and humPcMab-6-f exerted ADCC and complement-dependent cellular cytotoxicity in the presence of effector cells and complements, respectively. In the PDAC xenograft model, both PcMab-6-mG_2a-f and humPcMab-6-f exhibited potent antitumor effects. These results indicated that humPcMab-6-f could apply to antibody-based therapy against PODXL-expressing pancreatic cancers.

Pancreatic cancer has a poor prognosis with its five-year survival rate lower than that of any other cancer type because it is difficult to detect in the early stages. Gemcitabine, a standard treatment for pancreatic cancer, often has poor outcomes for patients as a result of chemoresistance. Therefore, novel therapeutic targets must be identified to overcome gemcitabine-resistance. Here, we found that SLC38A5, a glutamine transporter, is more highly overexpressed in gemcitabine-resistant patients than in gemcitabine-sensitive patients. Furthermore, the deletion of SLC38A5 decreased the proliferation and migration of gemcitabine-resistant PDAC cells. We also found that the inhibition of SLC38A5 triggered the ferroptosis signaling pathway via RNA sequencing. Also, silencing SLC38A5 induced mitochondrial dysfunction and reduced glutamine uptake and glutathione (GSH) levels, and downregulated the expressions of GSH-related genes NRF2 and GPX4. The blockade of glutamine uptake negatively modulated the mTOR-SREBP1-SCD1 signaling pathway. Therefore, suppression of SLC38A5 triggers ferroptosis via two pathways that regulate lipid ROS levels. Similarly, we observed knockdown of SLC38A5 restored gemcitabine sensitivity by hindering tumor growth and metastasis in the orthotopic mouse model. Altogether, our results demonstrated that SLC38A5 could be a novel therapeutic target to overcome gemcitabine-resistance in PDAC therapy.

Pancreatic ductal adenocarcinoma (PDAC) is a ravaging disease whose poor prognosis requires a more detailed understanding of its biology to foster the development of effective therapies. The unsatisfactory results of treatments targeting cell proliferation and its related mechanisms suggested to rather focus on the inflammatory tumor microenvironment (TME). Here, we discuss the role of cancer secreted proteins in the complex TME tumor-stroma crosstalk, to sched lights on druggable molecular targets for the development of innovative, safer and more efficient therapeutic strategies.

Pancreatic cancer leads the most common lethal tumor in America. This lethality is related to limited treatment options. Conventional treatments involve a non-specific use of chemotherapeutical agents like 5-FU, capecitabine, gemcitabine, cisplatine, oxaliplatine, or irinotecan, that produce several side effects. This review we focus on the use of targeted nanoparticles as an alternative to the standard treatment for the pancreatic cancer. The principal objective of the use of nanoparticles is the reduction in side effects that conventional treatments produce, mostly because of their nonspecificity. Currently, several molecular markets of pancreatic cancer cells have been studied to target nanoparticles and improve the actual treatment. Therefore, properly functionalizated nanoparticles with specific aptamers or antibodies can be used to recognize pancreatic cancer cells and once cancer is recognized, these nanoparticles can attack the tumor by drug delivery, hyperthermia, or gene therapy.

Pancreatic cancer is a fatal disease with mortality rate of 5% and a with a limited survival rate of 5 years. Despite of the extensive efforts that has been made to cure the disease it still has been considered as ‘undruggable’. It is characterized by epithelial to dense stromal tumor formation however due to lack of diagnosis options and treatment test available to detect the disease to the point at which resection of the tumor is possible, it makes it the fourth leading cause of cancer related death. The unavailable information regarding the early detection of biological markers along with the increased invasive tumor, the inherit chemoresistance against medication radiation and chemotherapy stubbornly fail the therapeutic options available. These associated problems made the scientists to reevaluate the approaches that are currently in practice and take a step back to fully understand the basic biological pathways that are involved in the pancreatic cancer, the heterogeneity of the tumor itself along with expression and a number of mutations that are observed at different locations. Clinical trial along with new approaches are nowadays focus of research to treat this tumor. The review paper describes the basic cellular pathways involved in pancreatic cancer, the gene mutations and their expression having effect on the pathology of the diseases along with treatment options that are available to treat the tumor. These efforts will help with the expansion of our knowledge to undergo the clinical trial and the synthesis of novel medicines for the prognosis of the disease.

Cancer-associated fibroblasts (CAFs) in the tumor microenvironment perform glycolysis to produce energy, i.e., ATP. Since the origin of CAFs is unidentified, it is not determined whether the intracellular metabolism transitions from oxidative phosphorylation (OXPHOS) to glycolysis when normal tissue fibroblasts differentiate into CAFs. In this study, we established an experimental system and induced the in vitro differentiation of mesenchymal stem cells (MSCs) to CAFs. Additionally, we performed metabolomic and RNA-sequencing analyses before and after differentiation to investigate changes in the intracellular metabolism. Consequently, we discovered that OXPHOS, which was the primary intracellular metabolism in MSCs, was reprogrammed to glycolysis. In addition, we identified CAF-specific metabolites that were expressed during this reprogramming and determined their presence in the pancreatic tumor tissues of mouse models. Thus, we conclude that normal tissue fibroblasts that differentiate into CAFs undergo a metabolic reprogramming from OXPHOS to glycolysis. Moreover, we identified the CAF-specific metabolites expressed during metabolic reprogramming as potential future biomarkers for pancreatic cancer.

For monitoring of chimeric antigen receptor (CAR) T-cell therapies antigen-based CAR detection methods are usually applied. However, for each target-antigen a separate detection system is required. Furthermore, when monitoring CAR T-cells in the blood of patients treated with bispecific antibodies or T-cell engagers (bsAbs/BiTEs) recognize the same antigen, these methods producing false-positive results in clinical diagnostics. Anti-CAR-linker monoclonal antibodies (mAbs) targeting the linker sequence between the variable domains of the antigen binding CAR fragment, promise an universal and unbiased CAR detection. To test this, we analyzed clinical specimens of all BCMA- and CD19 targeting CAR T-cell products currently approved for clinical use. We found a highly specific and sensitive CAR detection by using anti-CAR-linker mAb in blood cells from patients treated with Ide-cel, Tisa-cel, Axi-cel, Brexu-cel, and Liso-cel. For Ide-cel and Tisa-cel the sensitivity was significant lower compared to antigen-based CAR detection assays. Strikingly, the specificity of anti-CAR linker mAb was not affected by the simultaneous presence of bispecific blinatumomab or teclistamab for Axi-cel, Brexu-cel, Liso-cel or Ide-cel, respectively. Cilta-cel (containing an monomeric G4S-CAR linker) could not be detected by anti-CAR linker mAb. In conclusion, anti-CAR-linker mAbs are highly specific and useful for CAR T-cell monitoring but not universal applicable.

Tertiary lymphoid structures (TLSs) have become the focus of antitumor immunity. However, the prognostic significance of TLSs in epithelial ovarian cancer (EOC) treated with primary debulking surgery (PDS) or interval debulking surgery (IDS) remains unelucidated. This retrospective study examined the prognostic value of TLSs in tumor tissues obtained during PDS and IDS. Pathological specimens were collected from patients with EOC who underwent PDS or IDS between 2017 and 2020 at the National Cancer Center Hospital East. The correlation of tumor-infiltrating lymphocyte frequency, TLS presence, and PD-L1 expression with progression-free survival (PFS) and overall survival (OS) and the correlation between TLS and PD-L1 expression were analyzed. Overall, 25 specimens (15 from PDS and 10 from IDS) were analyzed. The presence of TLS was associated with a significantly longer OS in patients who underwent PDS but not in patients who underwent IDS. No correlation was identified between TLS and PFS in patients with PDS or with IDS. However, TLS was positively correlated with PD-L1 positivity. The prognostic impact of TLS, specifically in pre-chemotherapy specimens, and a positive correlation between TLS and PD-L1 indicate the potential of TLS as a meaningful biomarker for understanding antitumor immunity and developing immunotherapy for EOC.

Pancreatic cancer (PC) is the most lethal type of cancer, it has the lowest 5-year survival rate among all other types of cancers. More than half of PC cases are diagnosed at an advanced stage due to PC’s insidious and non-specific symptoms. Surgery remains the most efficacious treatment option currently available, but only 10-20% of PC cases are resectable upon diagnosis. As of now, the sole biomarker approved by the United States Food and Drug Administration (US-FDA) for PC is carbohydrate antigen 19-9 (CA19-9); however, its use is limited use for early diagnosis. An in-creasing number of studies have investigated a combination of biomarkers. Lately, there has been considerable interest in the application of a liquid biopsy, including the utilization of microRNAs (miRNAs), circulating tumor DNA (ctDNA), and circulating tumor cells (CTCs). Screening for PC is indicated for high-risk patients; studies on new diagnostic models combined with biomarkers for early detection have also shown promising results for the ability of these models and biomarkers to aid clinicians in deciding on whether to start screening. This review seeks to provide a concise overview of the advancements in existing biomarkers and explore novel strategies for the early detection of PC.

Pancreatic cancer presents formidable challenges due to rapid progression and resistance to conventional treatments. Oncolytic viruses (OVs) selectively infect cancer cells and cause cancer cells to lyse, releasing molecules that can be identified by the host’s immune system. Moreover, OV can carry immune-stimulatory payloads such as interleukin-12 which when delivered locally can enhance immune system-mediated tumor killing. OV’s are very well tolerated by cancer patients due to their ability to selectively target tumors without affecting surrounding normal tissues. OV’s have recently been combined with other therapies including chemotherapy and immunotherapy to improve clinical outcomes. Several OVs including adenovirus, herpes simplex viruses (HSV), vaccinia virus, parvovirus, reovirus, and measles virus have been evaluated in preclinical and clinical settings for the treatment of pancreatic cancer. We evaluated the safety and tolerability of a replication-competent oncolytic adenoviral vector carrying two suicide genes (thymidine kinase, TK; and cytosine deaminase, CD) and human interleukin-12 (hIL12) in metastatic pancreatic cancer patients in a phase 1 trial. This vector was found to be safe and well-tolerated at the highest doses tested without causing any significant adverse events (SAE). Moreover, long-term follow-up studies indicated an increase in the overall survival (OS) in subjects receiving the highest dose of the OV. Our encouraging long-term survival data provide hope for patients with advanced pancreatic cancers, a disease that has not seen a meaningful increase in OS in the last five decades. In this review article, we highlight several preclinical and clinical studies and discuss future directions for optimizing OV therapy in pancreatic cancer. We envision OV-based gene therapy to be a game changer in the near future with the advent of newer generation OVs that have higher specificity and selectivity combined with personalized treatment plans developed under AI guidance.

Pancreatic cancer (pancreatic ductal adenocarcinoma: PDAC) is one of the most aggressive neoplastic diseases. Metformin use was associated with reduced pancreatic cancer incidence or better survival in diabetics. Metformin has been shown to inhibit PDAC cells survival and growth in vitro and in vivo. However, clinical trials using metformin failed to decrease pancreatic cancer progression in patients, raising important questions about molecular mechanisms that protect tumor cells from the antineoplastic activities of metformin. We confirm that metformin acts through inhibition of mitochondrial complex I, decreasing the NAD+/NADH ratio and that NAD+/NADH homeostasis determines metformin sensitivity in several cancer cell lines. Metabolites that can restore the NAD+/NADH ratio turned PDAC cells resistant to metformin. In addition, metformin treatment of PDAC cell lines induced a compensatory NAMPT expression increasing the pool of cellular NAD+. The NAMPT inhibitor FK866 sensitized PDAC cells to the antiproliferative effects of metformin in vitro and decreased cellular NAD+ pool. Intriguingly, FK866 combined with metformin increased survival in mice bearing KP4 cells xenografts but not in mice with PANC1 xenografts. Transcriptome analysis revealed that the drug combination reactivated genes in the p53 pathway and oxidative stress providing new insights about the mechanisms leading to cancer cell death.

Pancreatic cancer is a serious and aggressive type of cancer that affects the digestive system and has a low chance of survival. Although traditional treatment methods have achieved some efficacy, the survival rate of patients remains low. Therefore, exploring novel treatment strategies is important. This article looks at the research done on bioactive compounds and plant extracts for treating pancreatic cancer. Bioactive compounds, such as naringenin and ziyuglycoside II, have significant anticancer activity and exert anti-pancreatic-cancer effects by inducing cell apoptosis, inhibiting the cell cycle, and blocking signaling pathways. Plant extracts, such as epigallocatechin-3-gallate and resveratrol, also demonstrate good anti-pancreatic cancer activity and inhibit tumor growth and metastasis. Additionally, the combined application of bioactive compounds and plant extracts may result in improved therapeutic effects. This article aims to provide a theoretical basis for the application of bioactive compounds and plant extracts in the treatment of pancreatic cancer and to help guide future medical research and practice.

The present work consisted of an exploratory study aiming to evaluate in vitro the potential of AuNPs during Radiation Therapy (RT) in human pancreatic adenocarcinoma cells. AuNPs coated with hyaluronic and oleic acids (HAOA-AuNPs) or with bombesin peptides (BBN-AuNPs) were used. AuNPs were characterized by Atomic Force Microscopy (AFM) and Dynamic Light Scattering. BxPC-3 tumour cells were irradiated with a 6 MV X-rays beam, in the absence or presence of AuNPs. AFM showed that HAOA-AuNPs and BBN-AuNPs are spherical with a mean size of 83+-20 nm and 49+-12 nm, respectively. For RT alone, a reduction in cell viability of up to 33+-12% was obtained compared to the control (p ≤ 0.0001). HAOA-AuNPs alone at 200 and 400 μM showed a reduction in cell viability of 20+-4% and 35+-4%, respectively, while for BBN-AuNPs, at 50 and 200 μM, a reduction in cell viability of 25+-3% and 37+-3% was obtained, respectively, compared to the control (p < 0.0001). At 72 h post-irradiation, a decrease in cell viability of 26+-3% and 22+-2% between RT+HAOA-AuNPs at 400 μM and RT+BBN-AuNPs at 50 μM, compared to RT alone, was obtained (p < 0.004). The combination of RT with AuNPs led to a significant decrease in cell viability compared to the control, or RT alone, thus representing an improved effect.

Background: Although previous studies have implicated a role for the stool microbiome in cancer cachexia, the fecal microbiome has not been previously characterized for patients with pancreatic ductal adenocarcinoma (PDAC) and cachexia treated with nutritional interventions such as enteral feeding. Methods: The PANCAX-1 (NCT02400398) prospective trial enrolled 31 cachectic advanced PDAC patients to receive jejunal tube peptide-based diet for 12 weeks who were planned for palliative chemotherapy. Out of 16 evaluable patients, 62.5% receiving enteral feeding met the primary endpoint of weight stability at 12 weeks. As part of an exploratory analysis of the PANCAX-1 trial, serial stool and blood samples were collected at 0 (C1D1), 6 (C2D1), and 12 (C3D1) weeks over the 12-week period of enteral feeding. Stool samples were analyzed using 16S v4 sequencing of the microbiome. Up to 219 plasma metabolites were analyzed by mass spectrometry and high-performance liquid chromatography. Results: A total of 29 stool samples were prospectively collected from 16 subjects with PDAC enrolled in PANCAX-1 who were evaluable for weight stability. Over 12 weeks of enteral feeding, statistically significant increases in the abundance of bacterial genera such as Veillonella (p=0.0150) and Actinomyces (p=0.0390) were observed, while there was a lower abundance of Bacteroides (p=0.0150) and Butyricicoccus (p=0.0390). Greater abundance of Veillonella and reduced Bifidobacterium at baseline were linked to greater weight stability. Plasma metabolomics in 10 subjects showed that weight unstable patients had significantly decreased levels of essential (L-histidine, L-phenylalanine) and non-essential amino acids (L-citrulline, L-tyrosine, all p<0.05) at the end of 12 weeks of enteral feeding. High stool Veillonella abundance was significantly associated with increases in the nucleotide 2-deoxycytidine 5-diphosphate and essential amino acid L-isoleucine but decreased TCA cycle metabolite alpha-ketoglutarate (all p<0.05). Conclusions: We are the first to demonstrate the feasibility of stool microbiome profiling and plasma metabolomics in paired stool and plasma samples from a prospective cohort of advanced PDAC patients on enteral feeding as their primary source of nutrition. Our findings are hypothesis-generating in that metabolites unique to weight stability and abundance of stool bacterial genera may inform future studies of anti-cachexia therapies involving enteral feeding or microbial modulation.

Therapeutic resistance in pancreatic ductal adenocarcinoma (PDAC) can be attributed, in part, to a dense extracellular matrix containing excessive collagen deposition. Here, we describe a novel Salmonella typhimurium (ST) vector expressing the bacterial collagenase Streptomyces omiyaensis trypsin (SOT), a serine protease known to hydrolyze collagens I and IV, which are predominantly found in PDAC. Utilizing aggressive models of PDAC, we show that ST-SOT selectively degrades intratumoral collagen leading to enhancement of immune checkpoint blockade (ICB) therapy in tumor-bearing mice. Ultimately, we found that ST-SOT treatment significantly modifies the intratumoral immune landscape to generate a microenvironment more conducive to ICB.

As a part of our ongoing research on endophytic fungi, we have isolated a sesterterpene mycotoxin, fusaproliferin (FUS), from Fusarium solani strain associated with the plant Aglaonema hookerianum Schott. FUS showed rapid and sub-micromolar IC₅₀ against pancreatic cancer cell lines. Time dependent survival analysis and microscopy imaging showed rapid morphological changes in cancer cell lines 4 hours after incubation with FUS. This provides a new chemical scaffold that can be further developed to obtain more potent synthetic agents against pancreatic cancer.

Recent studies have demonstrated an important role for vitamin C in the epigenetic regulation of cancer-related genes via DNA demethylation by the ten-eleven translocation (TET) methylcytosine dioxygenase enzymes. DNA methyltransferase (DNMT) reverses this, increasing DNA methylation and decreasing gene expression. Dual oxidase (DUOX) enzymes produce hydrogen peroxide (H2O2) in normal pancreatic tissue but are silenced in pancreatic cancer (PDAC). Treatment of PDAC with pharmacologic ascorbate (P-AscH-, intravenous, high dose vitamin C) increases DUOX expression. We hypothesized that inhibiting DNMT may act synergistically with P-AscH- to further increase DUOX expression and cytotoxicity of PDAC. PDAC cells demonstrated dose-dependent increases in DUOX mRNA and protein expression when treated with DNMT inhibitors. PDAC cells treated with P-AscH- + DNMT inhibitors demonstrated increased DUOX expression, increased intracellular oxidation, and increased cytotoxicity in vitro and in vivo compared to either treatment alone. These findings suggest a potential therapeutic, epigenetic mechanism to treat PDAC.

We conducted a retrospective evaluation of the clinical outcomes and prognostic factors in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) treated with first-line androgen receptor signaling inhibitors (ARSI) in real-world clinical practice in Japan. Between 2012 and 2023, a total of 127 consecutive patients with nmCRPC received ARSI treatment. Overall survival (OS), metastatic-free survival (MFS), and prostate-specific antigen progression–free survival (PSA-PFS) from ARSI initiation were assessed using Kaplan–Meier methodology. Clinical factors associated with OS in nmCRPC were analyzed using the Cox proportional hazards model. Among the patients, 72, 26, 12, and 17 received enzalutamide (ENZ), abiraterone (ABI), apalutamide (APA), and darolutamide (DARO) as first-line therapy. The median OS and MFS for all patients were 79.0 and 42.0 months, respectively. Median PSA-PFS was 27.0, 20.0, 10.0, and 14.0 months for patients treated with ENZ, ABI, APA, and DARO, respectively (p = 0.33). Multivariate analysis revealed that a baseline PSA level ≥3.67 ng/ml at ARSI initiation was significantly associated with poorer OS (p = 0.002). ARSI demonstrated favorable efficacy in nmCRPC patients. There were no significant differences in clinical outcomes among different types of ARSI therapy for nmCRP. Elevated baseline PSA at ARSI initiation was significantly associated with poorer OS.

Background: There is ongoing debate regarding the usefulness of laparoscopic pancreaticoduodenectomy. This study aimed to analyze all the randomized control trials published including the most recent one. Material and methods: The study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and MOOSE guidelines. Heterogeneity was measured using Q tests and I2. The random-effects models were used to summarise the relative risks, odds ratios, and mean differences as appropriate.Results:4 RCTs were included consisting of 818 patients. 411 patients were in the laparoscopic group and 407 in the open pancreaticoduodenectomy group. Weighted baseline patient characteristics were similar except more patients with pancreatic adenocarcinoma and more males were there in the open pancreaticoduodenectomy group. There was no difference in-hospital stay,90 days complications rate, 90 days mortality, R1 resection, postoperative pancreatic fistula, delayed gastric emptying, post pancreatectomy hemorrhage, bile leak between the two groups. Operative time was more in the laparoscopic group. Blood loss [mean difference -132.12 ml (-172.60,-91.65)] and surgical site infection [Risk ratio 0.41 ( 0.17-1.0)] were significantly lesser in laparoscopic group.Conclusion:There was no benefit in-hospital stay or clinical outcomes after laparoscopic pancreaticoduodenectomy. Blood loss and surgical site infection were lesser in laparoscopic pancreaticoduodenectomy.

Multi-step evolution characterizes the carcinogenesis of GI malignancies, where the disease progresses through the accrual of genetic mutations, co-option of multiple host cellular factors and the acquisition of increasingly aggressive pathological features. Ensuing cancer complexity and plasticity are challenges for therapeutic approaches. On the other hand, disease inception is often triggered by a defined oncogenic event, which leads to escalating effects on gene expression, cellular metabolism, chromatin organization and ultimately cell identity. Decoding this molecular cascade of events is crucial to design strategies for early diagnosis as well as to tackle tumor onset. To this aim, the in vitro culture of non-transformed epithelial cells represents a major technical challenge. Genetic studies, combined with lineage-tracing experiments demonstrated that pancreatic cancerous lesions originate from acinar cells, a specialized cell type in the pancreatic epithelium, following mutations of the KRAS oncogene. Ex vivo culture of pancreatic acinar cells has allowed the identification of early mutant KRAS-driven alterations. Primary acinar cells survive in vitro in organoid-like 3D spheroids, which can recapitulate histological and molecular features of disease initiation. Here, we will discuss the isolation and culture of primary mouse pancreatic acinar cells, providing and historical and technical perspective. Impact for pancreatic cancer research will also be debated; in particular we will dissect the role of KRAS signaling in driving oncogenic transformation and highlight differences with canonical 2D culture of established cancer cell lines.

Breast cancer poses a global health challenge, yet the influence of ethnicity on the tumor microenvironment (TME) remains understudied. In this investigation, we examined immune cell infiltration in 230 breast cancer samples, emphasizing diverse ethnic populations. Leveraging tissue microarrays (TMAs) and core samples, we applied multiplex immunofluorescence (mIF) to dissect immune cell subtypes across TME regions. Our analysis revealed distinct immune cell distribution patterns, particularly enriched in aggressive molecular subtypes triple-negative and HER2-positive tumors. We observed significant correlations between immune cell abundance and key clinicopathological parameters, including tumor size, lymph node involvement, and patient overall survival. Notably, immune cell location within different TME regions showed varying correlations with clinicopathologic parameters. Additionally, ethnicities exhibited diverse distributions of cells, with certain ethnicities showing higher abundance compared to others. In TMA samples, patients of Chinese and Caribbean origin displayed significantly lower numbers of B cells, TAMs, and FOXP3-positive cells. These findings highlight the intricate interplay between immune cells and breast cancer progression, with implications for personalized treatment strategies. Moving forward, integrating advanced imaging techniques, and exploring immune cell heterogeneity in diverse ethnic cohorts can uncover novel immune signatures and guide tailored immunotherapeutic interventions, ultimately improving breast cancer management.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths. Classically, liver transplantation (LT) can be curable for HCC tumors within the Milan criteria. Bridging strategies to reduce the dropouts from LT waiting lists or/and to downstage patients who are beyond Milan criteria are widely utilized. We conducted a literature-based review to evaluate the role of systemic therapies as a bridging treatment to liver transplantation (LT) in HCC patients. Tyrosine Kinase Inhibitors (TKIs) can be used as a bridging systemic therapy to LT in patients with contraindication to locoregional liver-directed therapies. Immune Checkpoint Inhibitors (ICIs) treatment can be utilized either as a monotherapy or as a combination therapy with Bevacizumab or TKIs prior to LT. Acute rejection post liver transplantation is a concern in the context of ICIs treatment. Thus, a safe ICI washout period before LT and cautious post-LT immunosuppression strategies are required to reduce post-LT rejections and to optimize clinical outcomes. Nevertheless, prospective clinical trials are needed to establish definitive conclusions about the utility of systemic therapy as a bridging modality prior to LT in HCC patients.

The p53 tumor suppressor protein is an activator of transcription. Diverse stress factors lead to various sets of posttranslational modifications of p53 what results in different sets of upregulat-ed genes. We noticed that actinomycin D and nutlin-3a (A+N) synergize in inducing activating phosphorylations of p53 and upregulation of selected p53-target genes. Here we found that one of these genes is DUSP13, which codes for poorly-studied, dual-specificity phosphatase having at least two isoforms, one expressed in testis and the other in skeletal muscles. In cancer cells ex-posed to A+N, DUSP13 is expressed from an alternative promoter in intron, what results in ex-pression of isoform named TMDP-L1. The luciferase reporter tests demonstrated that this pro-moter is activated by both endogenous and ectopically expressed p53. We showed for the first time that mRNA expressed from this promoter actually produces the protein, which can be de-tected by Western blotting in all examined cancer cell lines with wild-type p53 exposed to A+N. In some cell lines it is also induced by clinically relevant camptothecin or by nutlin-3a acting alone. This isoform, fused with green fluorescent protein localizes in perinuclear region of cells. Thus, TMDP-L1 isoform may be an important element of p53-regulated stress response system.

Cellular senescence accumulates with age and has been shown to impact numerous physiological and pathological processes, including immune function. The role of cellular senescence in cancer is multifaceted, but the impact on immune checkpoint inhibitor response and toxicity has not been fully evaluated. In this review, we evaluate the impact of cellular senescence in various biological compartments, including the tumor, the tumor microenvironment, and the immune system on immune checkpoint inhibitor efficacy and toxicity. We provide an overview of the impact of cellular senescence in normal and pathological contexts and examine recent studies that have connected aging and cellular senescence to immune checkpoint inhibitor treatment in both the pre-clinical and clinical contexts. Overall, senescence plays a multi-faceted, context-specific role, and has been shown to modulate immune-related adverse event incidence as well as immune checkpoint inhibitor response.

Quality-of-life (QOL) is important for cancer patients with poor prognosis. However, QOL survey is difficult using patients. We created cancer scenarios and investigated QOL utility values among the general public using vignette-based methods. On the other hand, some scenarios may have been difficult for the general public to image and understand. Therefore, we conducted a QOL survey among physicians. This survey was conducted by interviewing physicians adminis-tering chemotherapy to patients for recurrent/metastatic pancreatic cancer. Responses were eval-uated using Composite Time Trade-Off (cTTO) and Visual Analog Scale (VAS) for 11 pancreatic cancer status scenarios to be evaluated (survey scenarios). Survey scenarios consisted of health state, type and Grade of adverse events. Health status was classified into two categories: Stable disease (SD) and Progressive disease (PD). Twenty responders answered in this survey, however two responses were excluded because of inconsistent responses. The stable disease had the highest QOL value for both assessment method. Whereas progression disease (PD) had the lowest QOL value. The physicians scored higher QOL values on VAS and cTTO than the general public in all survey scenarios. The QOL values obtained by physicians were consistent with the degree of sta-tus in any assessment scenarios.

It has now known that at least 10% of samples with pancreatic cancers (PC) contain a causative mutation in the known susceptibility genes, suggesting the importance of identifying cancer-associated genes that carry the causative mutations in high-risk individuals for early detection of PC. In this study, we develop a statistical pipeline using a new concept, called gene-motif, that utilizes both mutated genes and mutational processes to identify 4,211 3-nucleotide PC-associated gene-motifs within 203 significantly mutated genes in PC. Using these gene-motifs as distinguishable features for pancreatic cancer subtyping results in identifying five PC subtypes with distinguishable phenotypes and genotypes. Our comprehensive biological characterization reveals that these PC subtypes are associated with different molecular mechanisms including unique cancer related signaling pathways, in which for most of the subtypes targeted treatment options are currently available. Some of the pathways we identified in all five PC subtypes, including cell cycle and the Axon guidance pathway are frequently seen and mutated in cancer. We also identified Protein kinase C, EGFR (epidermal growth factor receptor) signaling pathway and P53 signaling pathways as potential targets for treatment of the PC subtypes. Altogether, our results uncover the importance of considering both the mutation type and mutated genes in the identification of cancer subtypes and biomarkers.

Background: Pancreatic neuroendocrine tumors (pNETs) represents a rare subset of pancreatic cancer. Functional tumors caused hormonal changes and clinical syndromes, while non-functional ones are often diagnosed late. Surgical management need a multidisciplinary planning, involving enucleation, distal pancreatectomy with or without spleen preserving, cen-tral pancreatectomy, pancreaticoduodectomy or total pancreatectomy. Minimally invasive ap-proach increased in the last decade compared to the open technique. The aim of this study is to analyze current diagnostic and surgical trends for pNETs, to identify better interventions and their outcomes. Methods: The study adhered to PRISMA guidelines, conducting a systematic review of literature from May 2008 to March 2022 across multiple databases. Several combinations of keywords was used ("NET", "pancreatic", "surgery", "laparoscopic", "minimally invasive", "robotic”, “enuclea-tion”,“parenchima sparing”) and relevant article references was manually checked. Manuscript quality was evaluated. Results: The study screened 3867 manuscripts, twelve studies were selected, primarily from Ita-ly, the United States, and China. A total of 7767 surgical treated patients was collected from 160 included centers. The mean age was 56,3 y.o. Enucleations (EN) and distal pancreatectomy (DP) was the most common performed surgery and represents 43.4% and 38.6% of the total interven-tions, respectively. Pancreatic fistula, post operative bleeding, re-operation and follow up was recorded and analyzed. Conclusions: Enucleation show better postoperative outcomes and lower mortality rates com-pared to pancreaticoduodenectomy (PD) or distal pancreatectomy (DP), despite similar risks of postoperative pancreatic fistula (POPF). DP was preferred over enucleation for pancreas body-tail, while laparoscopic enucleation is better for head pNETs.

1) Background: When women receive a diagnosis of a gynecologic malignancy, they can have questions about their diagnosis or treatment that can result in voice queries to virtual assistants. Recent advancement in artificial intelligence (AI) has transformed the landscape of medical information accessibility. The Google virtual assistant (VA) outperformed Siri, Alexa, and Cortana in voice queries presented prior to the explosive implementation of AI in early 2023. The efforts presented here focus on determining if advances in AI in the last 12 months improved the accuracy of Google VA responses related to gynecologic oncology. (2) Methods: Previous questions were utilized to form a common basis for queries prior to 2023 and responses in 2024. Correct answers were obtained from the UpToDate medical resource. Responses related to gynecologic oncology were obtained using Google VA, as well as the generative AI chatbots Google Bard/Gemini and Microsoft Bing-Copilot. (3) Results: The AI narrative responses varied in length and positioning of answers within the response. Google Bard/Gemini achieved an 87.5% accuracy rate, while Microsoft Bing-Copilot reached 83.3%. In contrast, the Google VA’s accuracy in audible responses improved from 18% prior to 2023 to 63% in 2024. (4) Conclusion: While the accuracy of the Google VA has improved in the last year, it underperformed Google Bard/Gemini and Microsoft Bing-Copilot so that there is considerable room for further improved accuracy.

Background: In high-risk breast cancer patients with skin infiltration the administration of a uniform dose to superficial tissues is fundamental in order to reduce local skin relapse. A personalized bolus may prevent the potential standard bolus’ inadequate dose distribution due to air gaps between the bolus and the skin. In this pilot study, we introduced in clinical practice the use of a personalized 3D printed bolus filled with ultrasound transmission gel. Methods: Seven patients undergoing radiotherapy after mastectomy were selected. 3D printed bolus dosimetric assessment was performed with MOSFET dosimeters on an anthropomorphic phantom and subsequently on three selected cases with increasing bolus shape irregularity. Acute/late toxicity and local control was assessed. Results: Overall, for the clinical cases the percentage median difference between measured and calculated doses was -2.7% (-7.0%÷4.9%). Median follow-up was 21 months. After two years, one patient showed G2 pain, one patient manifested G1 telangiectasia, one patient showed G1 hyperpigmentation, and two patients had no relevant toxicity. Conclusions: Personalized 3D-printed bolus filled with ultrasound gel may easily reproduce the standard bolus’ consistency providing an accurate coverage of the target area with tolerable acute/late toxicity grades. This is a pilot study and further investigations are needed.

Expression of miR-21 has been found to be altered in almost all types of cancers and it has been classified as an oncogenic microRNA. In addition, expression of tumor suppressor gene RECK is associated with miR-21 overexpression in high-grade cervical lesions. In the present study we analyze the role of miR-21 in RECK gene regulation in cervical cancer cells. To identify the downstream cellular target genes of upstream miR-21, we silenced endogenous miR-21 expression using siRNAs. We analyzed the expression of miR-21 and RECK, as well as functional effects on cell proliferation and migration. We found that in cervical cancer cells there was an inverse correlation between miR-21 expression and RECK mRNA and protein expression. SiRNAs to miR-21 increased luciferase reporter activity in construct plasmids containing the RECK-3′-UTR microRNA response elements MRE21-1, MRE21-2, and MRE21-3. The role of miR-21 in cell proliferation was also analyzed and cancer cells transfected with siRNAs exhibited a markedly reduced cell proliferation and migration. Our findings indicate that miR-21 post-transcriptionally down-regulates the expression of RECK to promote cell proliferation and cell migration inhibition in cervical cancer cell survival. Therefore, miR-21 and RECK may be potential therapeutic targets in gene therapy for cervical cancer.

Accurate prostate volume estimation is crucial for effective prostate disease management. Ultrasound (US) imaging, particularly transrectal ultrasound, offers a cost-effective and rapid assessment. However, US images often suffer from artifacts and poor contrast, making prostate volume estimation challenging. This review explores recent advancements in deep learning (DL) techniques for automatic prostate segmentation in US images as a primary step for prostate volume estimation. We examine various DL architectures, including traditional U-Net modifications and innovative designs incorporating residual connections, multi-directional image data, and attention mechanisms. Additionally, we discuss pre-processing methods to enhance image quality, the integration of shape information, and strategies to improve the consistency and robustness of DL models. The effectiveness of these techniques is evaluated through metrics such as Dice Similarity Coefficient, Jaccard Index, and Hausdorff Distance. The review highlights the potential of DL in improving prostate volume estimation accuracy and reducing clinical workload, while also identifying areas for future research to enhance model performance and generalizability.

Background: Ovarian mesonephric-like adenocarcinoma (MLA) is a newly described histological type known for its aggressive behavior. This study aims to determine the frequency of ovarian MLA, review existing literature, and elucidate its clinicopathological characteristics, including potential therapeutic targets. Methods: We retrospectively reviewed the pathological diagnoses of 516 primary ovarian cancer surgical cases at our institution from 2010 to 2023. MLAs exhibiting typical morphological and immunohistochemical features were included. The frequency and clinicopathological characteristics of these cases were summarized. Additionally, we conducted a literature search using PubMed to collect and summarize previously reported cases of ovarian MLA. Results: Among the 516 primary ovarian cancer cases, we identified 3 cases (0.6%) of MLA. The patients were 52-76 years old, and the initial FIGO stages were IC1 (2 cases) and IIIB (1 case). All cases exhibited HRP, pMMR, PD-L1 negativity (CPS&lt;1), and HER2-low expression. Two cases experienced metastatic recurrence. A literature review identified 97 cases of MLA. MLA frequently exhibited KRAS mutations (90%, 38/42), with a recurrence rate of 39% (26/67). Conclusion: MLA accounted for 0.6% of malignant ovarian tumors at our institution, all of which were advanced or recurrent cases. These cases showed HRP, pMMR, and PD-L1 negativity, indicating a lack of current therapeutic targets. Literature also reports a high incidence of advanced and recurrent cases, highlighting the need for accurate diagnosis and the development of new treatments. The frequent KRAS mutations suggest a potential therapeutic target for recurrent or metastatic MLA.

Hydroperoxides (ROOH) are known as damaging agents capable of mediating mutation, while a role as signaling agents through oxidation of protein sulfhydryls that can alter cancer-related pathways has gained traction. Glutathione peroxidase 2 (GPX2) is an antioxidant enzyme that reduces ROOH at the expense of glutathione (GSH). GPX2 is noted for a tendency of large in-creases or decreases in expression levels during tumorigenesis that leads to investigators focusing on its role in cancer. However, GPX2 is only one component of multiple enzyme families that metabolize ROOH and GPX2 levels are often very low in the context of these other ROOH reducing activities. Colorectal cancer (CRC) was selected as a case study for examining GPX2 function as colorectal tissues and cancers are sites where GPX2 is highly expressed. A case can be made for a significant impact of changes in expression levels. There is also a link between GPX2 and NADPH oxidase 1 (NOX1) from earlier studies that is seldom addressed and is discussed, presenting data on a unique association in colon and CRC. Tumor-derived cell lines are quite commonly used for pre-clinical studies involving the role of GPX2 in CRC. Generally, selection for this type of work is limited to identifying cell lines based on high and low GPX2 expression with the standard re-search scheme of overexpression in low expressing lines and suppression in high expressing lines to identify impacted pathways. This overlooks CRC subtypes among cell lines involving a wide range of gene expression profiles and a variety of driver mutation differences along with a large difference in GPX2 expression levels. A trend for low and high GPX2 expressing cell lines to segregate into different CRC subclasses, indicated in this report, suggests that choices based solely on GPX2 levels may provide misleading and conflicting results by disregarding other properties of cell lines and failing to factor in differences in potential protein targets of ROOH. CRC and cell line classification schemes are presented here that were intended to assist workers in performing pre-clinical studies but are largely unnoted in work on GPX2 and CRC. Studies are often initiated on the premise that the transition from normal to CRC is associated with up-regulation of GPX2. This is probably correct. However, the source normal cells for CRC could be almost any colon cell type, some with very high GPX2 levels. These factors are addressed in this study.

First-line treatment for advanced large-cell neuroendocrine carcinoma of the lung (LCNEC) has limited efficacy. This study aimed to explore the efficacy and safety of everolimus combined with EP regimen chemotherapy (etoposide + cisplatin, EP) in the first-line treatment for LCNEC. The patients were randomly assigned to the experimental or control group, with 20 patients in each group. The experimental group received the mTOR inhibitor everolimus 5 mg once a day combined with EP ivgtt, d1-3, every 3 weeks for 4–6 cycles. The control group received EP only and the infusion method was the same as that of the experimental group. The safety in the experimental group was controllable and not inferior to that in the control group. Serious adverse effects were observed in approximately 10% of patients. Objective response rate (ORR) for the experimental and control groups were 15% vs. 0 (P=0.231), disease control rate (DCR) was 100% vs. 32% (P

Current treatments in patients with pancreatic cancer offer limited benefits. In this report, we applied “alkalization therapy”, which was efficacious for other solid tumors at our clinic, to stage 4 pancreatic cancer patients, and investigated its effect on disease prognosis. Patients with metastatic pancreatic cancer who were treated at Karasuma Wada Clinic in Kyoto, Japan, between 2011 and 2022 were included in the study. All patients received alkalization therapy (combination of an alkaline diet, bicarbonate, and citric acid administration), alongside standard chemotherapy. Urine samples were collected to assess urine pH as a marker for whole-body alkalization. In the 98 patients analyzed, the median overall survival (OS) from the time of diagnosis was 13.2 months. Patients with a mean urine pH of 7.5 or greater had a median OS of 29.9 months, compared with 15.2 months for those with a mean urine pH of 6.5 to 7.5, and 8.0 months for those with a mean urine pH of less than 6.5, which suggests a trend of a longer OS in patients with a higher urine pH. Conclusions: Alkalization therapy may offer a viable approach to enhance the survival of stage 4 pancreatic cancer patients, who typically have an unfavorable prognosis.

Pancreatic cancer (PC) is one of the most lethal forms of cancers with 5-year mean survival rate of less than 10%. Most of the PC associated deaths are due to metastasis to secondary sites. Calcium (Ca²⁺) signaling plays a critical role in regulating hallmarks of cancer progression including cell proliferation, migration and apoptotic resistance. Store operated Ca²⁺ entry (SOCE) mediated by Orai1/2/3 channels is a highly regulated and ubiquitous pathway responsible for Ca²⁺ influx into non-excitable cells. In this study, we performed extensive bioinformatic analysis of publicly available datasets and observed that Orai3 expression is inversely associated with the mean survival time of PC patients. Orai3 expression analysis in a battery of PC cell lines corroborated its differential expression profile. We then carried out thorough Ca²⁺ imaging experiments in 6 PC cell lines and found that Orai3 forms a functional SOCE in PC cells. Our in vitro functional assays show that Orai3 regulates PC cell cycle progression, apoptosis and migration. Most importantly, our in vivo xenograft studies demonstrate a critical role of Orai3 in PC tumor growth and secondary metastasis. Mechanistically, Orai3 controls G₁ phase progression, matrix metalloproteinase expression and epithelial-mesenchymal transition in PC cells. Taken together, this study for the first time reports that Orai3 drives aggressive phenotypes of PC cells i.e. migration in vitro and metastasis in vivo. Considering that Orai3 expression is inversely associated with the PC patients survival time, it appears to be a highly attractive therapeutic target.

Early detection of PDAC remains challenging due to the lack of early symptoms and absence of reliable biomarkers. The aim of the present project was to identify miRNA and proteomics sig-natures discriminating PDAC patients with DM from nondiabetic PDAC patients. Proteomics analysis and miRNA array were used for protein and miRNA screening. We used western blot-ting and Real-Time Quantitative Reverse Transcription polymerase chain reaction (qRT-PCR) for protein and miRNA validation. Comparisons between experimental groups with normal dis-tributions were performed using one-way ANOVA followed by Tukey’s post hoc test and pair-wise tests were performed using t tests. P≤0.05 was considered statistically significant. Protein cluster of differentiation 166 (CD166), glycoprotein CD63 (CD63), S100 calcium binding protein A13 (S100A13), and tumor necrosis factor-β (TNF-β) were detected in the proteomics screening. The miRNA assay revealed a differential miRNA 1285 regulation. Previously described in the literature target proteins of miR-1285 cadherin-1 (CDH-1), cellular Jun (c-Jun), p53, mothers against decapentaplegic homolog 4 (Smad4), human transglutaminase 2 (TGM2) and yes-associated protein (YAP), were validated via Western blotting. miR-1285-3p was successfully validated as differentially regulated in PDAC + DM via qRT-PCR. Overall, our data suggest miRNA1285-3p, TGM2, CDH-1, CD166 and S100A13 as potential meaningful biomarker candi-dates to characterize patients with PDAC + DM. Data are available via ProteomeXchange with identifier PXD053169.

During recent years there is an on-going deployment of 5G base stations for radiofrequency (RF) communication in Sweden as well in many other countries. This is made without investigations on risks to human health and the environment. Since 2016 we have made several measurements of environmental exposure to RF radiation in Stockholm, Sweden, including previous generations and now also 5G. In the current study, performed in October 2023, the broadband meter Narda-550 with the probe EF-1891 was used. It gives results in the root mean square (RMS) mode, thus not peak levels. Both the International Commission on Non-Ionizing Radiation Protection (ICNIRP) and the US Federal Communications Commission (FCC) base their guidelines on RMS levels of RF radiation. Measurements were made in similar city areas as in our previous studies. Results show that the RF radiation has increased substantially. High maximum levels were found at e.g. the Central Railway Station (3 637 191 µW/m2), and popular walking streets such as Mäster Samuelsgatan (11 613 976 µW/m2), and Drottninggatan (5 271 555 µW/m2). The peak values would be much higher. These levels are in the same magnitude or even higher than those measured in homes of persons that rapidly developed symptoms of the microwave syndrome after installation of 5G, usually in combination with 4G+, in the neighborhood. They are also substantially higher than levels that have previously been linked to cancer and the microwave syndrome in studies of people living near base stations and masts from previous generations of telecommunications.

Pancreatic ductal adenocarcinoma (PDAC) is mostly diagnosed at advanced or even metastasized stages limiting patient´s prognosis. Metastasis requires high tumor cell plasticity implying phenotypic switching in response to changing environments. Here, Epithelial-Mesenchymal-Transition (EMT), being associated with the gain of cancer stem cell (CSC) properties, and its reversion are important. Since it is poorly understood whether different CSC-phenotypes exist along the EMT-axis and how these impact malignancy-associated properties, we aimed to characterize CSC-populations of epithelial and mesenchymal PDAC cells. Single-cell cloning revealed CSC (Holoclone) and non-CSC (Paraclone) clones from the PDAC cell lines Panc1 and Panc89. Panc1 Holoclone cells showed a mesenchymal phenotype dominated by high expression of the stemness marker Nestin, while Panc89 Holoclone cells exhibited a SOX2-dominated epithelial phenotype. Panc89 Holoclone cells showed enhanced cell growth and self-renewal capacity but slow cluster-like invasion. Contrarily, Panc1 Holoclone cells showed slower cell growth and self-renewal ability but were highly invasive. Moreover, cell variants differentially responded to chemotherapy. In vivo, Panc1 and Panc89 cell variants significantly differed regarding number and size of metastases as well as organ manifestation leading to different survival outcomes. Overall, these data support the existence of different CSC-phenotypes along the EMT-axis in PDAC manifesting in different metastatic propensities.

In metastatic pancreatic cancer patients non eligible to surgery, signal-targeted therapies so far failed to show a significant amelioration of survival. These therapeutic options were tested in Phase II/III clinical trials mostly in combination with the reference treatment Gemcitabine. These innovative therapies aim at annihilating the oncogene dependency; they also aim at renormalizing the tumoral stroma to allow immune cell function or re-vascularisation. Transcriptomics and genomics large scale analysis show the great heterogeneity of pancreatic cancers and failed to clearly delineate specific oncogene dependency besides oncogenic Kras. In this review, we will describe the most recent proteomic data in pancreatic tumors and its metastasis, which could help at identifying their major signalling dependencies, as well as explain why they are intrinsically resistant to signal-targeted therapies. We will also discuss why PI3K signalling, as a paradigm of pro-tumorigenic cell signalling and of tumoral adaptative resistance to drugs, is a relevant target in this context.

In metastatic pancreatic cancer patients non eligible to surgery, signal-targeted therapies so far failed to show a significant amelioration of survival. These therapeutic options were tested in Phase II/III clinical trials mostly in combination with the reference treatment Gemcitabine. These innovative therapies aim at annihilating the oncogene dependency; they also aim at renormalizing the tumoral stroma to allow immune cell function or re-vascularisation. Transcriptomics and genomics large scale analysis show the great heterogeneity of pancreatic cancers and failed to clearly delineate specific oncogene dependency besides oncogenic Kras. In this review, we will describe the most recent proteomic data in pancreatic tumors and its metastasis, which could help at identifying their major signalling dependencies, as well as explain why they are intrinsically resistant to signal-targeted therapies. We will also discuss why PI3K signalling, as a paradigm of pro-tumorigenic cell signalling and of tumoral adaptative resistance to drugs, is a relevant target in this context.

: Optical coherence tomography is a non-invasive imaging technique that provides three-dimensional visualization of subsurface tissue structures. OCT has been proposed and explored in literature as a tool to assess oral cancer status, select biopsy sites, or identify surgical margins. Our endoscopic OCT device can generate widefield (centimeters long) imaging of lesions at any location in the oral cavity – but it is challenging for raters to quantitatively assess and score large volumes of data. Leveraging a previously developed epithelial segmentation network, this work develops quantifiable biomarkers that provide direct measurements of tissue properties in three-dimensions. We hypothesize that features related to morphology, tissue attenuation, and contrast between tissue layers will be able to provide a quantitative assessment of disease status (dysplasia through carcinoma). This work retrospectively assesses seven biomarkers on a lesion-contralateral matched OCT dataset of lateral and ventral tongue (40 patients, 70 sites). Epithelial depth and loss of epithelial-stromal boundary visualization provide the strongest discrimination between disease states. The stroma optical attenuation coefficient provides distinction of benign lesions from dysplasia and carcinoma. The stratification biomarkers visualize subsurface changes which provides potential for future utility in biopsy site selection or treatment margin delineation.

Background: Radiotherapy in the head-and-neck area is one of the main curative treatment options. However, this comes at the cost of varying levels of normal tissue toxicity, affecting up to 80% of patients. Mucositis can cause pain, weight loss and treatment delay leading to worse outcomes and decreased quality of life. Therefore, there is an urgent need for an approach to predict normal mucosa response in patients prior to treatment. Methods: We here describe an assay to detect irradiation response in patient healthy oral mucosa tissue. Mucosa specimens from the oral cavity were obtained after surgical resection, cut into thin slices, irradiated, and cultured for three days. Seven samples were irradiated with X-ray and three additional samples were irradiated with both X-ray and protons. Results: Healthy oral mucosa tissue slices maintained normal morphology and viability for three days. We measured a dose-dependent response to X-ray irradiation and compared X-ray and proton irradiation in the same mucosa sample, using standardized automated image analysis. Furthermore, increased levels of inflammation inducing factors - major drivers in mucositis development - could be detected after irradiation. Conclusion: This model can be utilized for investigating mechanistic aspects of mucositis development and can be developed into an assay to predict radiation-induced toxicity in normal mucosa.

Pancreatic ductal adenocarcinoma (PDAC) represents an extremely aggressive type of cancer due in part to early invasion and metastasis, which in turn involves epithelial-mesenchymal transition (EMT) of the tumor cells. Prompted by the discovery that two PDAC-derived tumor cell lines of the quasi-mesenchymal subtype (PANC-1, MIA PaCa-2) exhibit neuroendocrine differentiation (NED), we asked whether NED is associated with EMT. Using quantitative real-time PCR and immunoblot analysis, we initially verified endogenous expression of various NED markers, i.e., chromogranin A (CHGA), synaptophysin (SYP), somatostatin receptor 2 (SSTR2) and SSTR5 in PANC-1 and MIA PaCa-2 cells. In HPDE6c7 normal pancreatic duct epithelial cells and in BxPC-3, another PDAC cell line with an epithelial phenotype, the expression of CHGA, SYP and neuron-specific enolase 2 (NSE) was either undetectable or much lower than in PANC-1 and MIA PaCa-2 cells. Parental cultures of PANC-1 cells exhibit EM plasticity (EMP) and harbor clonal subpopulations with different EMT phenotypes [Ungefroren et al 2022]. Monitoring the NED state of mesenchymal and epithelial PANC-1 subclones showed that the NE phenotype is more pronounced in M-type clones when compared to E-type ones. Inducing EMT in parental cultures of PANC-1 cells by treatment with transforming growth factor (TGF)-β1 repressed epithelial genes and co-induced mesenchymal and NED genes, except for SSTR5. Surprisingly, treatment with bone morphogenetic protein (BMP)-7 differentially affected gene expression in PANC-1 and MIA PaCa-2 cells. It synergised with TGF-β1 in the induction of vimentin, SNAIL, SSTR2 and NSE but antagonised it in the regulation of CHGA and SSTR5. From these data, we conclude that in EMT of PDAC cells mesenchymal and NED markers are co-regulated, and that mesenchymal-epithelial transition (MET) is associated with a loss of both the mesenchymal and NED phenotypes. Analysing NED in another tumor type, small cell carcinoma of the ovary hypercalcemic type (SCCOHT), revealed that two model cell lines of this disease (SCCOHT-1, BIN-67) do express CDH1, SNAI1, VIM, CHGA, SYP, ENO2 and SSTR2, but that in contrast to BMP-7 none of these genes was transcriptionally regulated by TGF-β1. We conclude that in PDAC-derived tumor cells, NED is closely linked to EMT and TGF-β signaling, which may have implications for the therapeutic use of TGF-β inhibitors in PDAC management.

B-cell lymphoid malignancies is a heterogeneous group of hematologic cancers, where Bruton's tyrosine kinase (BTK) inhibitors have received FDA approval for several subtypes. The first-in-class covalent BTK inhibitor, ibrutinib, binds to the C481 amino acid residue to block the BTK enzyme and prevent the downstream signaling. Resistance to covalent BTK inhibitors can occur through mutations at the BTK binding site (C481S) but also other BTK sites and the phospholipase C gamma 2 (PLCγ2) resulting in downstream signaling. To bypass the C481S mutation, non-covalent BTK inhibitors, such as pirtobrutinib, were developed and are active against both wild-type and the C481S mutation. In this review, we discuss the molecular and genetic mechanisms which contribute to acquisition of resistance to covalent and non-covalent BTK inhibitors. In addition, we discuss the new emerging class of BTK degraders, which utilize the evolution of proteolysis-targeting chimeras (PROTACs) to degrade the BTK protein and constitute an important avenue of overcoming resistance. The moving landscape of resistance to BTK inhibitors and the development of new therapeutic strategies highlight the ongoing advances, that are being made towards the pursue of cure of B-cell lymphoid malignancies.

Recent epidemiologic studies have revealed an upward trend in young-onset colorectal cancer (YOCRC) overall, whereas specific data on young-onset colorectal neuroendocrine neoplasms (YONEN) remain limited. This study investigates demographic characteristics and survival trends in YONEN and compares these with those of young-onset colorectal adenocarcinoma (YOADC), the most common histologic subtype of YOCRC. A retrospective analysis was conducted from 2000 to 2019 using the Surveillance, Epidemiology, and End Results (SEER) database. Survival outcomes were assessed using univariate and multivariable Cox proportional models, with demographic differences evaluated via Wilcoxon Rank Sum and Chi-square tests. Out of 61,705 patients aged 20-49 with colorectal cancer, 8% had NEN, and 92% had adenocarcinoma. The YONEN cohort had a higher proportion of Black patients and a lower proportion of White patients than the YOADC cohort (21% vs. 13% and 44% vs. 57%, respectively). NEN was more commonly found in the rectum (79%), and adenocarcinoma was mostly colonic (57%) in origin. YONEN patients had better survival than YOADC patients. Multivariate analysis in YONEN patients revealed that Hispanic patients had better overall survival compared to White patients (HR 0.67, 95% CI 0.47-0.95, p=0.024). Racial disparities should be investigated further to aid in policymaking and targeted interventions.

Elizabethkingia anophelis is an opportunistic pathogen causing lifethreatening infections in humans, particularly in immunocompromised patients, neonates and elderly. Infections caused by this species are exceptionally challenging to treat due to its multiresistance to antimicrobials. We report a case of central line-associated bloodstream infection by E. anophelis in a 2.5-year-old girl with acute lymphoblastic leukemia successfully treated with a combination of piperacillin/tazobactam and amikacin. The literature was also reviewed on paediatric infections caused by E. anophelis. Accurate identification with MALDI-TOF, or using molecular techniques, is crucial because of varying susceptibilities among species. Early, accurate diagnosis and prompt effective treatment optimize outcomes.

This review provides an overview of eXplainable AI (XAI) methods for oncological ultrasound image analysis and compares their performance evaluations. A systematic search of Medline Embase and Scopus between March 25 and April 14 2024 identified 17 studies describing 14 XAI methods, including visualization, semantics, example-based, and hybrid functions. These methods primarily provided specific, local, and post-hoc explanations. Performance evaluations focused on AI model performance, with limited assessment of explainability impact. Standardized evaluations incorporating clinical end-users are generally lacking. Enhanced XAI transparency may facilitate AI integration into clinical workflows. Future research should develop real-time methodologies and standardized quantitative evaluative metrics.

Background: The patients with cancer, especially pancreas cancer, are frequently associated with thrombosis which is one of causes for poor outcome, and hypercoagulability exists in cancer patients. Hypercoagulability is considered to be caused by thrombin burst. Methods: Activated partial thromboplastin time (APTT), small amount of tissue factor induced FIX activation (sTF/FIXa) assays and thrombin time (TT) using clot waveform analysis (CWA) were performed in 138 patients with malignant neoplasm including pancreas cancer and 66 non-cancer patients. Results: Thrombosis was frequently associated in pancreas cancer and was observed in stage I. CWA-APTT showed that the peak times and heights were markedly long and heigh, respectively, in cancer patients, and the peak times were significantly longer in pancreas cancer patients than benign pancreas diseases, and the 1st DPH was significantly higher in pancreas cancers than other cancers or benign pancreas diseases. CWA-sTF/FIXa showed that the peak times and heights were longer and higher, respectively, in patients with cancer than those without cancers, and that the 1st DPH was significantly higher in pancreas cancers than in other cancers. CWA-TT showed that the peak times were significantly shorter in cancer patients than in healthy volunteers and that the peak heights were significantly higher in cancer than in benign pancreas diseases. Conclusions: Cancer patients including pancreas cancer were frequently associated with thrombosis due to hypercoagulability with thrombin burst detected by CWA.

Neuroblastoma (NB) is a childhood cancer with heterogeneous characteristics, posing challenges to effective treatment. NBs express somatostatin receptors that facilitates the use of somatostatin analogs (SSTAs) as tumor-seeking agents for diagnosis and therapy. High-risk (HR) NBs often have gain-of-function mutations in the receptor tyrosine kinase anaplastic lymphoma kinase (ALK). Despite intensive multimodal treatment, survival rates remain below 40% for children with HR-NB. The aim of this work was to investigate the combined effect of the SSTA 177Lu-octreotide with the ALK inhibitor lorlatinib. Mice bearing human HR-NB CLB-BAR tumors were treated with lorlatinib, 177Lu-octreotide, combination of these pharmaceuticals or saline (control). Tumor volume was monitored and tumor samples were evaluated for cleaved caspase-3 and expression of 84 human genes involved in apoptosis. Combination treatment with 177Lu-octreotide and lorlatinib demonstrated synergistic antitumor effects. Increased number of cleaved caspase 3-positive cells was observed in tumors from mice treated with 177Lu-octreotide alone and in combination with lorlatinib. Modulation of Bcl-2 family gene expression was observed only in the presence of both 177Lu-octreotide and lorlatinib, with BID downregulated and HRK upregulated on days 2 and 7, respectively. The data suggests that ALK signaling pathway inhibition may contribute to radiosensitization in radionuclide therapy with 177Lu-octreotide.

Abstract: Ovarian cancer (OC) ranks as the fifth most common cancer among women in the United States and globally, posing a significant health threat. Reactive oxygen species (ROS) have emerged as critical factors in the pathophysiology of this malignancy. ROS, characterized by their instability due to an unpaired electron, are involved in essential cellular functions and play a crucial role in the immune response under normal physiological conditions. However, an imbalance in ROS homeostasis, leading to excessive ROS production, results in oxidative stress (OS), which can cause indiscriminate damage to cellular structures and contribute to the pathogenesis of specific diseases, including OC. OC is primarily classified based on the originating cell type into epithelial, stromal, and germinal tumors, with epithelial tumors being the most prevalent. Despite advancements in medical technology, early detection of OC remains challenging, often leading to delayed treatment initiation. Current therapeutic approaches include surgical excision of tumor tissue, radiotherapy and chemotherapy. While these treatments are effective in early-stage OC, high mortality rates and frequent relapse underscore the urgent need for novel diagnostic and therapeutic strategies. This review aims to elucidate the role of ROS in OC, emphasizing the potential for developing innovative diagnostic tools and treatments that target ROS-mediated pathways. Given the critical impact of early detection and effective treatment, advancing our understanding of ROS in the context of OC could significantly enhance patient outcomes.

The healthcare domain is increasingly adopting IoT and Electronic Health Record (EHR) systems, generating vast volumes of healthcare data. This shift is driven by the growing need of delivering the right information to the right individuals, at the right time. The latter underscores the importance of adopting a comprehensive strategy for efficiently collecting, utilizing, and analyzing health-related data to not only enhance overall healthcare management but also for the provision of timely and personalized prevention strategies. The latter is of highest importance especially in scenarios where lack of effective treatments or poor survival rates (such in pancreatic cancer) renders typical healthcare strategies ineffective. In this article, we introduce an innovative and integrated platform that is specifically designed and developed for accessing, processing, and analyzing data in challenging healthcare scenarios, such as dealing with pancreatic cancer. This platform, called iHelp, combines multidisciplinary technologies and provides healthcare professionals reliable risk modelling, analysis, and prediction techniques so that individuals (at risk of developing pancreatic cancer) can be provided with timely, reliable, and personalized prevention and intervention measures. A key innovation in the iHelp platform is the standardized data management approach called Holistic Health Records (HHRs) that facilitate the capturing of all health determinants in a standardized and well-structured way for processing towards the provision of health risk detection and personalized healthcare decision support. In the development of iHelp platform, the HHRs are evaluated through different real-world healthcare datasets, including datasets coming from hospital systems, data from wearables, questionnaires, and mobile applications.

Pancreatic cancer is a refractory cancer with limited treatment options. Various cancer types are resistant to the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Eugenol, the main component of clove oil, exhibits anticancer, anti-inflammatory, and antioxidant effects. However, no studies have reported that eugenol increases TRAIL sensitivity by upregulating death receptor (DR) expression. Here, we aimed to investigate eugenol as a potent TRAIL sensitizer. Increased apoptosis and inhibition of cell proliferation was observed in pancreatic cancer cells treated with eugenol and TRAIL compared with those treated with eugenol alone. Eugenol upregulated the expression of DR5, inhibited FLICE-inhibitory protein (FLIP), an anti-apoptotic protein, and increased p53, a tumor suppressor protein. In addition, eugenol induced the generation of reactive oxygen species (ROS) and caused endoplasmic reticulum (ER) stress. C/EBP-homologous protein (CHOP) knockdown using siRNA decreased the expression of DR5 and reduced the combined effects of eugenol and TRAIL. These results demonstrate that eugenol enhances TRAIL-induced apoptosis by upregulating DR5 through the ROS-mediated ER stress-CHOP pathway, enhancing ER stress by inducing p53 and downregulating FLIP expression. This suggests that eugenol has the potential to treat pancreatic cancer by increasing cell sensitivity to TRAIL.

Arsenic trioxide (ATO) has been shown to inhibit pancreatic cell growth in vitro and to promote the inhibitory effects of gemcitabine on pancreatic cancer in vivo. However, the high toxicity of ATO associated with the required high doses and indiscriminate targeting has limited its clinical application. This study aimed to determine whether coupling arsenic to a tumor homing peptide would increase the inhibitory potency against pancreatic cancer cells. The effects of this peptide-linked arsenic compound and ATO on pancreatic cancer growth were tested in vitro and in a mouse model. The data demonstrated that the peptide-linked arsenic compound inhibited pancreatic cancer cell growth more potently with IC50 values 10 times lower than ATO. Like ATO, the peptide-linked compound induced cell death and cell cycle arrest. More importantly, the peptide-linked arsenic compound inhibited pancreatic cancer growth in mice and enhanced the inhibitory effect of gemcitabine on pancreatic cancer growth at 2 times lower molar concentration than ATO. These results indicate that the peptide-linked arsenic compound inhibited pancreatic cancer more potently than ATO and suggest a potential clinical use for the combination of gemcitabine with the peptide-linked arsenic compound for the treatment of pancreatic cancer.

Cancer associated cachexia (CAC) is a critical contributor to pancreatic ductal adenocarcinoma (PDAC) mortality. Thus, there is an urgent need for new strategies to mitigate PDAC-associated cachexia; and the exploration of dietary interventions is a critical component. We previously observed that a ketogenic diet (KD) combined with gemcitabine enhances overall survival in the autochthonous LSL-KrasG12D/+; LSL-Trp53 R172H/+; Pdx1-Cre (KPC) mouse model. In this study, we investigated the effect and cellular mechanisms of a KD in combination with gemcitabine on the maintenance of skeletal muscle mass in KPC mice. For this purpose, male and female pancreatic tumor-bearing KPC mice were allocated to a control diet (CD), a KD, a CD + gemcitabine (CG), or a KD + gemcitabine (KG) group. We observed that a KD or a KG mitigated muscle strength decline over time and presented higher gastrocnemius weights compared CD-fed mice. Mechanistically, we observed sex-dependent effects of KG treatment, including the inhibition of autophagy, and increased phosphorylation levels of eIF2α in KG-treated KPC mice when compared to CG-treated mice. Our data suggests that a KG results in preservation of skeletal muscle mass. Additional research is warranted to explore whether this diet-treatment combination can be clinically effective in combating CAC in PDAC patients.

The current study aimed to investigate the antitumor effects and potent mechanism of cytokine-induced killer (CIK) cells combined with irreversible electroporation (IRE) via an in vitro function assay in an in vivo Panc02 cell–bearing mouse model. We established an in vitro culture assay for CIK cells and determined the proportions of different peripheral lymphocytes. The antitumor effect of the combination of IRE and CIK cells in a Panc02 pancreatic-cancer (PC) subcutaneous-xenograft model was investigated; tumor size and mouse survival rates were recorded. We used flow cytometry (FCM) to analyze the proportion of intratumoral lymphocytes, the expression of chemokine receptors, and the proliferative activity of CIK cells. The proportion of cells that were positive for clusters of differentiation 3 and 8 (CD3+CD8+) and the proportion of CD3+CD56+ cells were both significantly increased after 21 days of in vitro culture. Combined IRE/CIK cell treatment significantly inhibited tumor growth and increased the survival rate of Panc02 cell–bearing mice. Furthermore, infiltration of lymphocytes into tumor tissue was significantly increased by this combination therapy compared with the untreated group or monotherapy group. In addition, IRE significantly enhanced the expression of chemokine receptors elicited by, and the proliferative activity of, CIK cells. In conclusion, IRE combined with CIK cells showed superior antitumor efficacy in a PC subcutaneous-xenograft model, which we attributed to the promotion of lymphocytic infiltration, as well as to upregulation of chemokine receptor expression and of regulators of CIK cell proliferation.

Retinoblastoma (Rb) is a rare cancer that nonetheless represents the most common ocular malignancy in children. Rb exists as familiar and sporadic cancer and the increasing incidence of the sporadic one and its pathogenesis is mostly unknown. To date the management of retinoblastoma requires intensive chemotherapy and sometimes invasive surgery in order to preserve vision and quality of life in Rb patients. The discovery of the epigenetic nature of non-hereditable/sporadic Rb led to the development of high-throughput precision investigation strategies for the study of its epigenetic landscape. Here we investigated the effect of the demethylating 5-Aza-2’- deoxycytidine (Decitabine; DAC) agent on preclinical models to assess its possible use as anti-cancer drug in the treatment of Rb patients. We found that DAC treatment induced cell cycle arrest and apoptosis in Weri-Rb-1 cells. We investigated the variation of differential gene expression profile in Rb cells in relation to time of exposure to DAC with respect to controls. Network map analysis evidences 15 hub/driver genes, which share pathways of regulation of TNF-, FAS-, p53-dependent apoptotic signaling and NF-kB pro-survival pathways. Furthermore, a computing expression profile analysis of publicly available datasets of patients’ primary tumors and normal retina cell-derived organoids vs WeriWeri-Rb-1 DEGs depicted the relevancy of these 15 hub genes on retinoblastoma genesis. The antiproliferative effect of DAC treatment on Rb was confirmed in vivo, both in subcutaneous xenograft and orthotopic models also showing the changes the gene methylation status in treated Weri-Rb-1, shedding a new light on the reprogramming antiproliferative dynamics induced by the epigenetic therapy and on the role of this therapeutic approach to spare children sight and life.

Cancer immunotherapy targeting immune checkpoints has exhibited promising clinical outcomes in many cancers, but it offers only limited benefits for pancreatic cancer (PC). Cancer stem cells (CSCs), a minor subpopulation of cancer cells, play important roles in tumor initiation, progression, and drug resistance. Accumulating evidence suggests that CSCs employ immunosuppressive effect to evade the immune recognition. However, clinical implications of the associations among CD8+ T cells infiltration, programmed death receptor ligand-1 (PD-L1) expression, and CSCs existence are poorly understood in PC. Immunostaining and quantitative analysis were performed to assess CD8+ T cells infiltration, PD-L1 expression, and their relationship with CD44+/CD133+ CSCs and disease progression in PC. CD8+ T cells infiltration was associated with better survival while PD-L1 expression was correlated with PC recurrence. Both the low CD8+ T cells infiltration/high PD-L1 expression group and the high CD8+ T cells infiltration/high PD-L1 expression group show high levels of CD44+/CD133+ CSCs, but patients with low CD8+ T cells infiltration/high PD-L1 expression had worse survival and higher recurrence risk than those with high CD8+ T cells infiltration/high PD-L1 expression. Moreover, CD8+ T cells infiltration could reduce unfavorable prognostic effect of high co-expression of PD-L1 and CD44/CD133. Our study highlights an interaction among CD8+ T cells infiltration, PD-L1 expression, and CD44+/CD133+ CSCs existence, which contributes to PC progression and immune evasion.

Background: Potential calcium-related adverse events of vitamin D supplement use have not been addressed in large-scale, real-world data so far. Methods: Leveraging data from the UK Biobank, encompassing 445,493 individuals aged 40-69, we examined associations of high 25-hydroxyvitamin (25[OH]D) levels ≥100 nmol/L and vitamin D supplementation with hypercalcemia (plasma calcium >2.6 mmol/L), kidney stones, and atherosclerosis assessments (pulse wave arterial stiffness index and carotid intima-medial thickness). Regression models were comprehensively adjusted for 49 covariates. Results: Approximately 1.5% of the participants had high 25(OH)D levels, 4.3% regularly used vitamin D supplements, and 20.4% reported regular multivitamin use. At baseline, the hypercalcemia prevalence was 1.6%, and 1.1% were diagnosed with kidney stones during follow-up. High 25(OH)D levels were neither associated with calcium-related adverse events nor atherosclerosis assessments. Vitamin D and multivitamin supplementation were associated with an increased prevalence of hypercalcemia (odds ratios and 95% confidence intervals: 1.46[1.32-1.62] and 1.11[1.04-1.18], respectively) but were neither associated with atherosclerosis nor future kidney stones. Conclusion: High 25(OH)D levels observable in routine care were not associated with any adverse outcome. Vitamin D users have a slightly higher prevalence of hypercalcemia, possibly due to co-supplementation with calcium, but without higher atherosclerosis prevalence or risk of kidney stones.

Purpose: To simplify the application of optical coherence tomography (OCT) for examination of subsurface morphology in the oral cavity and reduce barriers towards adoption of OCT as a biopsy guidance device. The aim of this work was to develop automated software tools for simplified analysis of the large volume of data collected during OCT. Methods: Imaging and corresponding histopathology were acquired in-clinic using a wide-field endoscopic OCT system. An annotated dataset (n = 294 images) from 60 patients (34 male, 26 female) was assembled to train four unique neural networks. A deep learning pipeline was built using convolutional and modified u-net models to detect the imaging field of view (network 1), detect artifacts (network 2), identify the tissue surface (network 3), and identify the presence and location of the basement membrane (network 4). Results: The area under the curve of the image and artifact detection networks was 1.00 and 0.94 respectively. The Dice similarity score for the surface and basement membrane segmentation networks was 0.98 and 0.83 respectively. Conclusion: Deep Learning (DL) techniques can identify the location and variations in the epithelial surface and basement membrane in OCT images of the oral mucosa. Segmentation results can be synthesized into accessible en face maps to allow easier visualization of changes.

This review explores the nuanced decision-making surrounding postoperative radiotherapy for diffuse low-grade glioma (DLGG) patients, emphasizing the need for personalized treatment to balance the benefits of tumor control with the risks of long-term side effects. Radiotherapy is a cornerstone of DLGG treatment, offering significant improvements in progression-free survival, but its potential for cognitive decline and vascular lesions necessitates careful consideration of individual patient factors. The review delves into the complexities of radiotherapy timing, revealing that while early radiotherapy enhances progression-free survival, it does not significantly impact overall survival and may lead to earlier onset of cognitive decline. Conversely, delayed radiotherapy may mitigate cognitive decline but may result in shorter progression-free survival and the onset of neurological symptoms. The review advocates for a patient-centered approach, emphasizing the importance of weighing individual risks and benefits, and highlights the potential of artificial intelligence in predicting cognitive decline and the need to revisit previous research findings in light of the 2021 WHO (World Health Organization) classification update, underscoring the evolving nature of DLGG treatment and the ongoing quest for optimal therapeutic strategies.

Inflammation and immune cell dysfunction are critical facilitators of endometriosis pathophysiology. The diverse cellular fractions in the endometriotic microenvironment are represented mainly by glands and stroma, which are infiltrated by immune cells, including macrophages. Macrophages are renowned for stimulating lesion growth, vascularization, and innervation and contributing to pain in the disorder. By combining macrophages and endometriotic cells, we determined if resveratrol and its natural analogs can target the immune dysregulation and oxidative imbalance in endometriosis. We studied the effect of analyzed compounds on the expression of key inflammatory and oxidative stress markers, cytokines release, and ROS production by applying q-PCR, ELISA, Cytometric Beads Array, and multiplexed fluorogenic staining and flow cytometry analysis with bioimaging. The results showed that endometriosis-related macrophages treated with resveratrol or its derivatives have impaired expression of pro-inflammatory markers such as IL6, IL8, IL1B, TNF, CCL2, CXCL10, and PTGS2. This study also reported a pronounced antioxidant effect of the compounds by reducing the accumulation of free radicals in macrophages, which correlated with the transcript activation of detoxification enzymes (SOD, GPx). Considering the harmful macrophage action in endometriosis, we described the prospects for potential therapy based on regulating the immune microenvironment and reducing the accumulation of free radicals.